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1.
  • Capela, J P, et al. (author)
  • Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia
  • 2006
  • In: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 139:3, s. 1069-1081
  • Journal article (peer-reviewed)abstract
    • Studies on 3,4-methylenedioxymethamphetamine ("ecstasy")-induced neurotoxicity mainly focus on damage of serotonergic terminals. Less attention has been given to neuronal cell death produced by 3,4-methylenedioxymethamphetamine and other amphetamines in areas including the cortex, striatum and thalamus. In the present study we investigated 3,4-methylenedioxymethamphetamine-induced neurotoxicity in neuronal serum free cultures from rat cortex. Since 3,4-methylenedioxymethamphetamine intake induces hyperthermia in both animals and humans, the experiments were performed under normal (36.5 degrees C) and hyperthermic conditions (40 degrees C). Our findings showed a dose-, time- and temperature-dependent apoptotic cell death induced by 3,4-methylenedioxymethamphetamine in cortical neurons. 3,4-Methylenedioxymethamphetamine-induced damage was potentiated under hyperthermia. The neurotoxicity was reduced by the serotonin 2A-receptor antagonists, ketanserin and (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrol idinol hydrochloride, in both normothermic and hyperthermic conditions. (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride, a model agonist for the serotonin 2A-receptor, also induced a dose- and time-dependent apoptotic cell death. Again, protection was provided by ketanserin and (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrol idinol hydrochloride against (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced neurotoxicity, thereby indicating that the 3,4-methylenedioxymethamphetamine stimulation of the serotonin 2A-receptor leads to neurotoxicity. This study provides for the first time evidence that direct 3,4-methylenedioxymethamphetamine serotonin 2A-receptor stimulation leads to neuronal cortical death. alpha-Phenyl-N-tert-butyl nitrone a free radical scavenger and the nitric oxide synthase inhibitor Nomega-nitro-L-arginine as well as the NMDA-receptor antagonist MK-801 provided protection under normothermia and hyperthermia, thereby suggesting the participation of free radicals in 3,4-methylenedioxymethamphetamine-induced cell death. Since 3,4-methylenedioxymethamphetamine serotonin 2A-receptor agonistic properties lead to neuronal death, clinically available atypical antipsychotic drugs with serotonin 2A-antagonistic properties could be a valuable therapeutic tool against 3,4-methylenedioxymethamphetamine-induced neurodegeneration.
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2.
  • Capela, Joao Paulo, et al. (author)
  • The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons
  • 2013
  • In: NeuroToxicology. - : Elsevier BV. - 1872-9711 .- 0161-813X. ; 34, s. 254-263
  • Journal article (peer-reviewed)abstract
    • 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) are hallucinogenic amphetamines with addictive properties. The hippocampus is involved in learning and memory and seems particularly vulnerable to amphetamine's neurotoxicity. We evaluated the neurotoxicity of DOI and MDMA in primary neuronal cultures of hippocampus obtained from Wistar rat embryos (E-17 to E-19). Mature neurons after 10 days in culture were exposed for 24 or 48 h either to MDMA (100-800 mu M) or DOI (10-100 mu M). Both the lactate dehydrogenase (LDH) release and the tetrazolium-based (MTT) assays revealed a concentration- and time-dependent neuronal death and mitochondrial dysfunction after exposure to both drugs. Both drugs promoted a significant increase in caspase-8 and caspase-3 activities. At concentrations that produced similar levels of neuronal death, DOI promoted a higher increase in the activity of both caspases than MDMA. In the mitochondrial fraction of neurons exposed 24 h to DOI or MDMA, we found a significant increase in the 67 kDa band of apoptosis inducing factor (AIF) by Western blot. Moreover, 24 h exposure to DOI promoted an increase in cytochrome c in the cytoplasmatic fraction of neurons. Pre-treatment with an antibody raised against the 5-HT2A-receptor (an irreversible antagonist) greatly attenuated neuronal death promoted by 48 h exposure to DOI or MDMA. In conclusion, hallucinogenic amphetamines promoted programmed neuronal death involving both the mitochondria machinery and the extrinsic cell death key regulators. Death was dependent, at least in part, on the stimulation of the 5-HT2A-receptors. (C) 2012 Elsevier Inc. All rights reserved.
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3.
  • Cheng, Fang, et al. (author)
  • Non-toxic amyloid beta formed in the presence of glypican-1 or its deaminatively generated heparan sulfate degradation products
  • 2013
  • In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 23:12, s. 1510-1519
  • Journal article (peer-reviewed)abstract
    • The amyloid beta (A beta) peptides (mainly A beta 40 and A beta 42), which are derived from the amyloid precursor protein (APP), can oligomerize into antibody A11-positive, neurotoxic species, believed to be involved in Alzheimer's disease. Interestingly, APP binds strongly to the heparan sulfate (HS) proteoglycan (PG) glypican-1 (Gpc-1) in vitro and both proteins are colocalized inside cells. In endosomes, APP is proteolytically processed to yield A beta peptides. The HS chains of S-nitrosylated (SNO) Gpc-1 PG are cleaved into anhydromannose (anMan)-containing di- and oligosaccharides by an NO-dependent reaction in the same compartments. Here, we have studied the toxicity of oligomers/aggregates of A beta 40 and A beta 42, as well as A beta 40/42 mixtures that were formed in the presence of immobilized Gpc-1 PG or immobilized HS oligosaccharides. Afterwards, A beta was displaced from the matrices, analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and assayed for A11 immunoreactivity, for effects on growth of mouse N2a neuroblastoma cells and for membrane leakage in rat cortical neurons. HS generally promoted and accelerated A beta multimerization into oligomers as well as larger aggregates that were mostly A11 positive and showed toxic effects. However, non-toxic A beta was formed in the presence of Gpc-1 PG or when anMan-containing HS degradation products were simultaneously generated. Both toxic and non-toxic A beta peptides were taken up by the cells but toxic forms appeared to enter the nuclei to a larger extent. The protection afforded by the presence of HS degradation products may reflect a normal intracellular function for the A beta peptides.
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4.
  • Christensen, Jakob Hakon, et al. (author)
  • Preservation of the blood brain barrier and cortical neuronal tissue by liraglutide, a long acting glucagon-like-1 analogue, after experimental traumatic brain injury.
  • 2015
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
  • Journal article (peer-reviewed)abstract
    • Cerebral edema is a common complication following moderate and severe traumatic brain injury (TBI), and a significant risk factor for development of neuronal death and deterioration of neurological outcome. To this date, medical approaches that effectively alleviate cerebral edema and neuronal death after TBI are not available. Glucagon-like peptide-1 (GLP-1) has anti-inflammatory properties on cerebral endothelium and exerts neuroprotective effects. Here, we investigated the effects of GLP-1 on secondary injury after moderate and severe TBI. Male Sprague Dawley rats were subjected either to TBI by Controlled Cortical Impact (CCI) or sham surgery. After surgery, vehicle or a GLP-1 analogue, Liraglutide, were administered subcutaneously twice daily for two days. Treatment with Liraglutide (200 μg/kg) significantly reduced cerebral edema in pericontusional regions and improved sensorimotor function 48 hours after CCI. The integrity of the blood-brain barrier was markedly preserved in Liraglutide treated animals, as determined by cerebral extravasation of Evans blue conjugated albumin. Furthermore, Liraglutide reduced cortical tissue loss, but did not affect tissue loss and delayed neuronal death in the thalamus on day 7 post injury. Together, our data suggest that the GLP-1 pathway might be a promising target in the therapy of cerebral edema and cortical neuronal injury after moderate and severe TBI.
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5.
  • Costa, João T., et al. (author)
  • Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABAA Receptor Clustering and Contributes to Neuronal Death
  • 2016
  • In: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 53:6, s. 3513-3527
  • Journal article (peer-reviewed)abstract
    • GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the central nervous system, and changes in GABAergic neurotransmission modulate the activity of neuronal networks. Gephyrin is a scaffold protein responsible for the traffic and synaptic anchoring of GABAA receptors (GABAAR); therefore, changes in gephyrin expression and oligomerization may affect the activity of GABAergic synapses. In this work, we investigated the changes in gephyrin protein levels during brain ischemia and in excitotoxic conditions, which may affect synaptic clustering of GABAAR. We found that gephyrin is cleaved by calpains following excitotoxic stimulation of hippocampal neurons with glutamate, as well as after intrahippocampal injection of kainate, giving rise to a stable cleavage product. Gephyrin cleavage was also observed in cultured hippocampal neurons subjected to transient oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia, and after transient middle cerebral artery occlusion (MCAO) in mice, a model of focal brain ischemia. Furthermore, a truncated form of gephyrin decreased the synaptic clustering of the protein, reduced the synaptic pool of GABAAR containing γ2 subunits and upregulated OGD-induced cell death in hippocampal cultures. Our results show that excitotoxicity and brain ischemia downregulate full-length gephyrin with a concomitant generation of truncated products, which affect synaptic clustering of GABAAR and cell death.
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6.
  • Durrant, Claire S., et al. (author)
  • Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling
  • 2020
  • In: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:2
  • Journal article (peer-reviewed)abstract
    • Amyloid beta peptides (Aβ) proteins play a key role in vascular pathology in Alzheimer’s Disease (AD) including impairment of the blood–brain barrier and aberrant angiogenesis. Although previous work has demonstrated a pro-angiogenic role of Aβ, the exact mechanisms by which amyloid precursor protein (APP) processing and endothelial angiogenic signalling cascades interact in AD remain a largely unsolved problem. Here, we report that increased endothelial sprouting in human-APP transgenic mouse (TgCRND8) tissue is dependent on β-secretase (BACE1) processing of APP. Higher levels of Aβ processing in TgCRND8 tissue coincides with decreased NOTCH3/JAG1 signalling, overproduction of endothelial filopodia and increased numbers of vascular pericytes. Using a novel in vitro approach to study sprouting angiogenesis in TgCRND8 organotypic brain slice cultures (OBSCs), we find that BACE1 inhibition normalises excessive endothelial filopodia formation and restores NOTCH3 signalling. These data present the first evidence for the potential of BACE1 inhibition as an effective therapeutic target for aberrant angiogenesis in AD.
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7.
  • Ejlerskov, Patrick, et al. (author)
  • Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia.
  • 2015
  • In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 163:2, s. 324-339
  • Journal article (peer-reviewed)abstract
    • Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-β promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-β overexpression prevented dopaminergic neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.
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8.
  • Flygt, Johanna, et al. (author)
  • Neutralization of Interleukin-1 beta following Diffuse Traumatic Brain Injury in the Mouse Attenuates the Loss of Mature Oligodendrocytes
  • 2018
  • In: Journal of Neurotrauma. - : MARY ANN LIEBERT, INC. - 0897-7151 .- 1557-9042. ; 35:23, s. 2837-2849
  • Journal article (peer-reviewed)abstract
    • Traumatic brain injury (TBI) commonly results in injury to the components of the white matter tracts, causing post-injury cognitive deficits. The myelin-producing oligodendrocytes (OLs) are vulnerable to TBI, although may potentially be replaced by proliferating oligodendrocyte progenitor cells (OPCs). The cytokine interleukin-1 beta (IL-1 beta) is a key mediator of the complex inflammatory response, and when neutralized in experimental TBI, behavioral outcome was improved. To evaluate the role of IL-1 beta on oligodendrocyte cell death and OPC proliferation, 116 adult male mice subjected to sham injury or the central fluid percussion injury (cFPI) model of traumatic axonal injury, were analyzed at two, seven, and 14 days post-injury. At 30 min post-injury, mice were randomly administered an IL-1 beta neutralizing or a control antibody. OPC proliferation (5-ethynyl 2 '- deoxyuridine (EdU)/Olig2 co-labeling) and mature oligodendrocyte cell loss was evaluated in injured white matter tracts. Microglia/macrophages immunohistochemistry and ramification using Sholl analysis were also evaluated. Neutralizing IL-1 beta resulted in attenuated cell death, indicated by cleaved caspase-3 expression, and attenuated loss of mature OLs from two to seven days post-injury in brain-injured animals. IL-1 beta neutralization also attenuated the early, two day post-injury increase of microglia/macrophage immunoreactivity and altered their ramification. The proliferation of OPCs in brain-injured animals was not altered, however. Our data suggest that IL-1 beta is involved in the TBI-induced loss of OLs and early microglia/macrophage activation, although not the OPC proliferation. Attenuated oligodendrocyte cell loss may contribute to the improved behavioral outcome observed by IL-1 beta neutralization in this mouse model of diffuse TBI.
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9.
  • Flygt, Johanna, 1985-, et al. (author)
  • Reduced loss of mature Oligodendrocytes following Diffuse Traumatic Brain Injury in the mouse by Neutralization of Interleukin-1β
  • Other publication (other academic/artistic)abstract
    • AbstractBackground: Traumatic brain injury (TBI) leads to several secondary consequences impairing patient outcome. Injury to the components of the white matter, the oligodendrocyte population, myelin and axons, associate with post-injury cognitive deficits. Oligodendrocytes (OLs), the myelin-producing cell, are highly vulnerable post-TBI. Lost OLs may be replaced by proliferating oligodendrocyte progenitor cells (OPCs). A complex inflammatory response is also initiated following TBI, which is an important therapeutic target in TBI. The cytokine, interleukin-1β (IL-1β), is a key mediator of the inflammatory response. When neutralized following experimental TBI, behavioral and histological outcome is improved by unknown mechanisms.Methods: The central fluid percussion injury (cFPI) and sham injury was used in mice at three survival end-points; 2, 7 and 14 days post-injury. Mice were, at 30 min post-injury, randomly administered a neutralizing IL-1β antibody or a control antibody.  OPC proliferation (5-ethynyl 2´- deoxyuridine (EdU)/Olig 2 co-labeling) and mature OL cell death was evaluated in injured white matter tracts. In situ hybridization for Olig2 transcripts in EdU positive cells and microglia ramification was also evaluated.Results: Attenuated cell death, indicated by cleaved caspase-3 expression, and OL cell loss was observed in brain-injured animals treated with the IL-1β neutralizing antibody without influencing proliferation of OPCs, the number of Olig2 transcript or the ramification of microglia.  Conclusion: Although OPC proliferation was not influenced, IL-1β neutralization reduced oligodendrocyte cell death in diffuse TBI which may partly explain the beneficial outcome observed using this anti-inflammatory treatment.    
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10.
  • Francardo, Veronica, et al. (author)
  • Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism
  • 2014
  • In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137, s. 1998-2014
  • Journal article (peer-reviewed)abstract
    • Sigma-1 receptor ligands may have neuroprotective and neurorestorative properties. In a mouse model of parkinsonism, Francardo et al. show that chronic treatment with the sigma-1 receptor agonist PRE-084 increases the density of striatal dopaminergic fibres and improves forelimb use. Boosting sigma-1 receptor activity may have disease-modifying effects in ParkinsonA ' s disease.The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma-1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma-1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson's disease.
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11.
  • Gard, Anna, et al. (author)
  • Cerebrospinal fluid levels of neuroinflammatory biomarkers are increased in athletes with persistent post-concussive symptoms following sports-related concussion
  • 2023
  • In: Journal of Neuroinflammation. - : Springer Nature. - 1742-2094. ; 20
  • Journal article (peer-reviewed)abstract
    • A sports-related concussion (SRC) is often caused by rapid head rotation at impact, leading to shearing and stretching of axons in the white matter and initiation of secondary inflammatory processes that may exacerbate the initial injury. We hypothesized that athletes with persistent post-concussive symptoms (PPCS) display signs of ongoing neuroinflammation, as reflected by altered profiles of cerebrospinal fluid (CSF) biomarkers, in turn relating to symptom severity. We recruited athletes with PPCS preventing sports participation as well as limiting work, school and/or social activities for ≥ 6 months for symptom rating using the Sport Concussion Assessment Tool, version 5 (SCAT-5) and for cognitive assessment using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Following a spinal tap, we analysed 27 CSF inflammatory biomarkers (pro-inflammatory chemokines and cytokine panels) by a multiplex immunoassay using antibodies as electrochemiluminescent labels to quantify concentrations in PPCS athletes, and in healthy age- and sex-matched controls exercising ≤ 2 times/week at low-to-moderate intensity. Thirty-six subjects were included, 24 athletes with PPCS and 12 controls. The SRC athletes had sustained a median of five concussions, the most recent at a median of 17 months prior to the investigation. CSF cytokines and chemokines levels were significantly increased in eight (IL-2, TNF-α, IL-15, TNF-β, VEGF, Eotaxin, IP-10, and TARC), significantly decreased in one (Eotaxin-3), and unaltered in 16 in SRC athletes when compared to controls, and two were un-detectable. The SRC athletes reported many and severe post-concussive symptoms on SCAT5, and 10 out of 24 athletes performed in the impaired range (Z < − 1.5) on cognitive testing. Individual biomarker concentrations did not strongly correlate with symptom rating or cognitive function. Limitations include evaluation at a single post-injury time point in relatively small cohorts, and no control group of concussed athletes without persisting symptoms was included. Based on CSF inflammatory marker profiling we find signs of ongoing neuroinflammation persisting months to years after the last SRC in athletes with persistent post-concussive symptoms. Since an ongoing inflammatory response may exacerbate the brain injury these results encourage studies of treatments targeting the post-injury inflammatory response in sports-related concussion.
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12.
  • Gisselsson, Lennart, et al. (author)
  • Rho kinase inhibition protects CA1 cells in organotypic hippocampal slices during in vitro ischemia.
  • 2010
  • In: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1316, s. 92-100
  • Journal article (peer-reviewed)abstract
    • The actin cytoskeleton is a dynamic superstructure that regulates multiple cellular functions and that has been implicated in cell death regulation. We investigated whether modulating the neuronal actin cytoskeleton polymerization by Rho GTPase kinase (ROCK) inhibition influences cell death in hippocampal neuronal cultures and in murine organotypic hippocampal slice cultures subjected to in vitro ischemia (IVI). During IVI, spines on vehicle treated hippocampal neurons collapsed and large dendritic actin aggregates were formed. Following ROCK inhibition by Y27632, the actin aggregates were markedly smaller while large filopodia extended from the dendritic trunk. Y27632 also provided strong neuroprotection of hippocampal pyramidal CA1 neurons, which was of similar magnitude as protection by NMDA receptor blockade. Likewise, treatment with the F-actin depolymerizing agent latrunculin during IVI diminished actin aggregation and mitigated cell death following IVI. We propose that ROCK inhibition protects neurons against ischemic damage by disrupting actin polymerization thereby mitigating NMDA receptor induced toxicity and releasing ATP bound to actin for cellular energy use. We conclude that ROCK inhibitors abrogate multiple detrimental processes and could therefore be useful in stroke therapy.
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13.
  • González-Manteiga, Ana, et al. (author)
  • A Novel In Vivo Model for Multiplexed Analysis of Callosal Connections upon Cortical Damage
  • 2022
  • In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:15
  • Journal article (peer-reviewed)abstract
    • Brain damage is the major cause of permanent disability and it is particularly relevant in the elderly. While most studies focused on the immediate phase of neuronal loss upon injury, much less is known about the process of axonal regeneration after damage. The development of new refined preclinical models to investigate neuronal regeneration and the recovery of brain tissue upon injury is a major unmet challenge. Here, we present a novel experimental paradigm in mice that entails the (i) tracing of cortico-callosal connections, (ii) a mechanical lesion of the motor cortex, (iii) the stereological and histological analysis of the damaged tissue, and (iv) the functional characterization of motor deficits. By combining conventional microscopy with semi-automated 3D reconstruction, this approach allows the analysis of fine subcellular structures, such as axonal terminals, with the tridimensional overview of the connectivity and tissue integrity around the lesioned area. Since this 3D reconstruction is performed in serial sections, multiple labeling can be performed by combining diverse histological markers. We provide an example of how this methodology can be used to study cellular interactions. Namely, we show the correlation between active microglial cells and the perineuronal nets that envelop parvalbumin interneurons. In conclusion, this novel experimental paradigm will contribute to a better understanding of the molecular and cellular interactions underpinning the process of cortical regeneration upon brain damage.
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14.
  • Gram, Magnus, et al. (author)
  • Hemoglobin induces inflammation after preterm intraventricular hemorrhage by methemoglobin formation.
  • 2013
  • In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 10:Aug.,6
  • Journal article (peer-reviewed)abstract
    • Cerebral intraventricular hemorrhage (IVH) is a major cause of severe neurodevelopmental impairment in preterm infants. To date, no therapy is available that prevents infants from developing serious neurological disability following IVH. Thus, to develop treatment strategies for IVH, it is essential to characterize the initial sequence of molecular events that leads to brain damage. In this study, we investigated extracellular hemoglobin (Hb) as a causal initiator of inflammation in preterm IVH.
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15.
  • Hakon, Jakob, et al. (author)
  • Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity
  • 2024
  • In: Brain : a journal of neurology. - 1460-2156. ; 147:1, s. 186-200
  • Journal article (peer-reviewed)abstract
    • Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function, and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischemia. Using multiple behavioral tests we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam, and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172, and accelerated in mGluR5 KO mice compared to wild-type mice. After stroke, multisensory stimulation by enriched environments (EE) enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in EE-mediated recovery. Additionally, MTEP treatment in conjunction with EE housing provided an additive recovery enhancement compared to either MTEP or EE alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy.
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16.
  • Hakon, Jakob, et al. (author)
  • Multisensory stimulation improves functional recovery and resting-state functional connectivity in the mouse brain after stroke
  • 2018
  • In: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 17, s. 717-730
  • Journal article (peer-reviewed)abstract
    • Stroke causes direct structural damage to local brain networks and indirect functional damage to distant brain regions. Neuroplasticity after stroke involves molecular changes within perilesional tissue that can be influenced by regions functionally connected to the site of injury. Spontaneous functional recovery can be enhanced by rehabilitative strategies, which provides experience-driven cell signaling in the brain that enhances plasticity. Functional neuroimaging in humans and rodents has shown that spontaneous recovery of sensorimotor function after stroke is associated with changes in resting-state functional connectivity (RS-FC) within and across brain networks. At the molecular level, GABAergic inhibitory interneurons can modulate brain plasticity in peri-infarct and remote brain regions. Among this cell-type, a decrease in parvalbumin (PV)-immunoreactivity has been associated with improved behavioral outcome. Subjecting rodents to multisensory stimulation through exposure to an enriched environment (EE) enhances brain plasticity and recovery of function after stroke. Yet, how multisensory stimulation relates to RS-FC has not been determined. In this study, we investigated the effect of EE on recovery of RS-FC and behavior in mice after stroke, and if EE-related changes in RS-FC were associated with levels of PV-expressing neurons. Photothrombotic stroke was induced in the sensorimotor cortex. Beginning 2 days after stroke, mice were housed in either standard environment (STD) or EE for 12 days. Housing in EE significantly improved lost tactile-proprioceptive function compared to mice housed in STD environment. RS-FC in the mouse was measured by optical intrinsic signal imaging 14 days after stroke or sham surgery. Stroke induced a marked reduction in RS-FC within several perilesional and remote brain regions. EE partially restored interhemispheric homotopic RS-FC between spared motor regions, particularly posterior secondary motor. Compared to mice housed in STD cages, EE exposure lead to increased RS-FC between posterior secondary motor regions and contralesional posterior parietal and retrosplenial regions. The increased regional RS-FC observed in EE mice after stroke was significantly correlated with decreased PV-immunoreactivity in the contralesional posterior motor region. In conclusion, experimental stroke and subsequent housing in EE induces dynamic changes in RS-FC in the mouse brain. Multisensory stimulation associated with EE enhances RS-FC among distinct brain regions relevant for recovery of sensorimotor function and controlled movements that may involve PV/GABA interneurons. Our results indicate that targeting neural circuitry involving spared motor regions across hemispheres by neuromodulation and multimodal sensory stimulation could improve rehabilitation after stroke.
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17.
  • Häggman Henrikson, Jens, et al. (author)
  • Enhanced functional recovery by levodopa is associated with decreased levels of synaptogyrin following stroke in aged mice
  • 2020
  • In: Brain Research Bulletin. - : Elsevier BV. - 0361-9230. ; 155, s. 61-66
  • Journal article (peer-reviewed)abstract
    • Levodopa is a precursor to dopamine that has been shown to improve functional recovery following stroke partly achieved through mechanisms of brain plasticity. This study investigates if dopamine might affect plasticity by having a direct effect on synaptic plasticity through alterations in neurotransmitter release and re-uptake. Synaptogyrin is a synaptic vesicle protein that has been suggested to be involved in dopamine re-uptake in the synaptic terminal. Therefore, we investigated if levodopa has an effect on the expression of synaptogyrin 1. Thy1-YFP mice were subjected to photothrombosis as an experimental model of stroke. Starting two days after surgery they were treated with either levodopa or a vehicle solution (saline) on a daily basis until day seven following surgery. On day seven they were sacrificed and their brains stained for Dopamine 1 receptor (D1R), Dopamine 2 receptor (D2R) and Parvalbumin (PV). Neu-N stainings were used to estimate infarct size. A second group of mice were subjected to photothrombosis and also treated with either levodopa or a vehicle solution in the same manner as previously mentioned. On day seven they were then sacrificed, and samples of brain tissue were taken for protein determination. Western blots were carried out to investigate possible differences in synaptogyrin expression between the two groups. Immunofluorescent stains showed the presence of dopamine receptors on the YFP-positive neurons and on PV-expressing neurones. Our Western Blot analysis showed a significant decrease in the expression of synaptogyrin in levodopa-treated mice. Our stains showed co-localisation with Thy-1 neurones and PV-expressing neurones for both D1 and D2 receptors. This indicates that dopamine has the ability to bind to, and directly influence cortical neurons, as well as inhibitory interneurons. We discovered a considerable decrease in synaptogyrin expression through levodopa treatment, suggesting that this might be a mechanism for regulating brain plasticity.
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18.
  • Inacio, Ana, et al. (author)
  • Enriched environment downregulates macrophage migration inhibitory factor and increases parvalbumin in the brain following experimental stroke
  • 2011
  • In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 41:2, s. 270-278
  • Journal article (peer-reviewed)abstract
    • Housing rodents in an enriched environment (EE) following experimental stroke enhances neurological recovery. Understanding the underlying neural cues may provide the basis for improving stroke rehabilitation. We studied the contribution of brain macrophage migration inhibitory factor (MIF) to functional recovery after permanent middle cerebral artery occlusion (pMCAo) in rats. In the cerebral cortex, MIF is predominantly found in neurons, particularly in parvalbumin interneurons. Following pMCAo, MIF increases around the infarct core, where it is located to neurons and astrocytes. Housing rats in an EE after pMCAo resulted in a decrease of MIF protein levels in pen-infarct areas, which was accompanied by an increase in parvalbumin immunoreactive interneurons. Our data suggest that MIF is part of a signaling network involved in brain plasticity, and elevated neuronal and/or astrocytic MIF levels repress the recovery of sensory-motor function after stroke. Downregulating MIF could constitute a new therapeutic approach to promote recovery after stroke. (C) 2010 Elsevier Inc. All rights reserved.
  •  
19.
  • Inacio, Ana, et al. (author)
  • Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke.
  • 2011
  • In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; Dec, s. 1093-1106
  • Journal article (peer-reviewed)abstract
    • Multiple mechanisms contribute to tissue demise and functional recovery after stroke. We studied the involvement of macrophage migration inhibitory factor (MIF) in cell death and development of neurologic deficits after experimental stroke. Macrophage migration inhibitory factor is upregulated in the brain after cerebral ischemia, and disruption of the Mif gene in mice leads to a smaller infarct volume and better sensory-motor function after transient middle cerebral artery occlusion (tMCAo). In mice subjected to tMCAo, we found that MIF accumulates in neurons of the peri-infarct region, particularly in cortical parvalbumin-positive interneurons. Likewise, in cultured cortical neurons exposed to oxygen and glucose deprivation, MIF levels increase, and inhibition of MIF by (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) protects against cell death. Deletion of MIF in Mif(-/-) mice does not affect interleukin-1β protein levels in the brain and serum after tMCAo. Furthermore, disruption of the Mif gene in mice does not affect CD68, but it is associated with higher galectin-3 immunoreactivity in the brain after tMCAo, suggesting that MIF affects the molecular/cellular composition of the macrophages/microglia response after experimental stroke. We conclude that MIF promotes neuronal death and aggravates neurologic deficits after experimental stroke, which implicates MIF in the pathogenesis of neuronal injury after stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 November 2010; doi:10.1038/jcbfm.2010.194.
  •  
20.
  • Ishizaki, Taku, et al. (author)
  • The asparaginyl endopeptidase legumain after experimental stroke.
  • 2010
  • In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; Apr 7, s. 1756-1766
  • Journal article (peer-reviewed)abstract
    • Various proteases in the brain contribute to ischemic brain injury. We investigated the involvement of the asparaginyl endopeptidase legumain after experimental stroke. On the basis of gene array studies and in situ hybridizations, we observed an increase of legumain expression in the peri-infarct area of rats after transient occlusion of the middle cerebral artery (MCAO) for 120 mins with a maximum expression at 24 and 48 h. Immunohistochemical analyses revealed the expression of legumain in Iba1(+) microglial cells and glial fibrillary acidic protein-positive astrocytes of the peri-infarct area in mice after MCAO. Post-stroke recovery was also studied in aged legumain-deficient mice (45 to 58 weeks old). Legumain-deficient mice did not show any differences in physiologic parameters compared with respective littermates before, during MCAO (45 mins), and the subsequent recovery period of 8 days. Moreover, legumain deficiency had no effect on mortality, infarct volume, and the neurologic deficit determined by the rotating pole test, a standardized grip strength test, and the pole test. However, a reduced number of invading CD74(+) cells in the ischemic hemisphere indicates an involvement in post-stroke inflammation. We conclude that legumain is not essential for the functional deficit after MCAO but may be involved in mechanisms of immune cell invasion.Journal of Cerebral Blood Flow & Metabolism advance online publication, 17 March 2010; doi:10.1038/jcbfm.2010.39.
  •  
21.
  • Kuric, Enida, et al. (author)
  • Dopamine receptor activation increases glial cell line-derived neurotrophic factor in experimental stroke.
  • 2013
  • In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 247:May,9, s. 202-208
  • Journal article (peer-reviewed)abstract
    • Treatment with levodopa enhances functional recovery after experimental stroke but its mechanisms of action are elusive. Reactive astrocytes in the ischemic hemisphere are involved in mechanisms promoting recovery and also express dopamine 1 (D1) and dopamine 2 (D2) receptors. Here we investigated if the activation of astrocytic dopamine receptors (D1 and D2) regulates the expression of glial cell line-derived neurotrophic factor (GDNF) after combined in vitro hypoxia/aglycemia (H/A) and studied the expression of GDNF in the ischemic brain after treatment with levodopa/benserazide following transient occlusion of the middle cerebral artery (tMCAO) in the rat. Twenty-four hours after H/A, GDNF levels were upregulated in exposed astrocytes compared to normoxic control cultures and further elevated by the addition of the selective D1 receptor agonist (R)-(+)-SKF-38393 hydrochloride while D1 receptor antagonism by R(+)-SCH-23390 hydrochloride significantly reduced GDNF. No effect on GDNF levels was observed by the application of the D2 receptor agonist R(-)-2,10,11-trihydroxy-N-propyl-noraporphine hydrobromide hydrate or S-(-)-eticlopride hydrochloride (D2 receptor antagonist). After tMCAO, GDNF was upregulated in D1 expressing reactive astrocytes in the peri-infarct area. In addition, treatment with levodopa/benserazide significantly increased GDNF levels in the infarct core and peri-infarct area after tMCAO without affecting the expression of glial fibrillar acidic protein (GFAP), an intermediate filament and marker of reactive gliosis. After stroke, GDNF levels increase in the ischemic hemisphere in rats treated with levodopa, implicating GDNF in the mechanisms of tissue reorganization and plasticity and in l-DOPA enhanced recovery of lost brain function. Our results support levodopa treatment as a potential recovery enhancing therapy in stroke patients.
  •  
22.
  • Kuric, Enida, et al. (author)
  • Dynamics of major histocompatibility complex class II-positive cells in the postischemic brain - influence of levodopa treatment
  • 2014
  • In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11
  • Journal article (peer-reviewed)abstract
    • Background: Cerebral ischemia activates both the innate and the adaptive immune response, the latter being activated within days after the stroke onset and triggered by the recognition of foreign antigens. Methods: In this study we have investigated the phenotype of antigen presenting cells and the levels of associated major histocompatibility complex class II (MHC II) molecules in the postischemic brain after transient occlusion of the middle cerebral artery (tMCAO) followed by levodopa/benserazide treatment. Male Sprague Dawley rats were subjected to tMCAO for 105 minutes and received levodopa (20 mg/kg)/benserazide (15 mg/kg) for 5 days starting on day 2 after tMCAO. Thereafter, immune cells were isolated from the ischemic and contralateral hemisphere and analyzed by flow cytometry. Complementarily, the spatiotemporal profile of MHC II-positive (MHC II+) cells was studied in the ischemic brain during the first 30 days after tMCAO; protein levels of MHC II and the levels of inflammation associated cytokines were determined in the ischemic hemisphere. Results: We found that microglia/macrophages represent the main MHC II expressing cell in the postischemic brain one week after tMCAO. No differences in absolute cell numbers were found between levodopa/benserazide and vehicle-treated animals. In contrast, MHC II protein levels were significant downregulated in the ischemic infarct core by levodopa/benserazide treatment. This reduction was accompanied by reduced levels of IFN-gamma, TNF-alpha and IL-4 in the ischemic hemisphere. In the contralateral hemisphere, we exclusively detected MHC II+ cells in the corpus callosum. Interestingly, the number of cells was increased by treatment with levodopa/benserazide independent from the infarct size 14 days after tMCAO. Conclusions: Results suggest that dopamine signaling is involved in the adaptive immune response after stroke and involves microglia/macrophages.
  •  
23.
  • Kuric, Enida, et al. (author)
  • Reduction of rat brain CD8(+) T-cells by levodopa/benserazide treatment after experimental stroke.
  • 2014
  • In: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 40:2, s. 2463-2470
  • Journal article (peer-reviewed)abstract
    • The activation of inflammatory cascades in the ischemic hemisphere impairs mechanisms of tissue reorganization with consequences for recovery of lost neurological function. Recruitment of T-cell populations to the post-ischemic brain occurs and represents a significant part of the inflammatory response. This study was conducted to investigate if treatment with levodopa, potentially acting as an immunomodulator, affects the T-cell accumulation in the post-ischemic brain. Male Sprague-Dawley rats were subjected to transient occlusion of the middle cerebral artery (tMCAO) for 105 min followed by levodopa/benserazide treatment (20 mg/kg/15 mg/kg) for 5 days initiated on day 2 post-stroke. One week after tMCAO, T-cell populations were analysed from brains, and levels of interleukin (IL)-1β, chemokine (C-X-C motif) ligand 1, IL-4, IL-5, interferon gamma and IL-13 were analysed. After levodopa/benserazide treatment, we found a significant reduction of cytotoxic T-cells (CD3(+) CD8(+) ) in the ischemic hemisphere together with reduced levels of T-cell-associated cytokine IL-5, while other T-cell populations (CD3(+) , CD3(+) CD4(+) , CD3(+) CD4(+) CD25(+) ) were unchanged compared with vehicle-treated rats. Moreover, a reduced number of cells was associated with reduced levels of intercellular adhesion molecule 1, expressed in endothelial cells, in the infarct core of levodopa/benserazide-treated animals. Together, we provide the first evidence that dopamine can act as a potential immunomodulator by attenuating inflammation in the post-ischemic brain.
  •  
24.
  • Kuric, Enida, et al. (author)
  • Reversal of stroke induced lymphocytopenia by levodopa/benserazide treatment.
  • 2014
  • In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 269:1-2, s. 94-97
  • Journal article (peer-reviewed)abstract
    • Evidences exist that dopamine is involved in T-cell homeostasis. Here, we investigated if daily treatment with levodopa (20mg/kg)/benserazide (15mg/kg) regulates the number of T-cells in the blood of Sprague Dawley rats subjected to transient occlusion of the middle cerebral artery (tMCAO). T-cells and associated inflammatory cytokines were analyzed in the blood one week after tMCAO. Treatment with levodopa/benserazide completely recovered T-helper cell depletion in animals subjected to tMCAO whereas T-cell associated cytokines remained unaffected after stroke, however, cytokines were downregulated in levodopa treated sham operated animals. Together, we demonstrate that dopamine has beneficial effects on poststroke immunodepression.
  •  
25.
  • Madinier, Alexandre, et al. (author)
  • Enriched housing enhances recovery of limb placement ability and reduces aggrecan-containing perineuronal nets in the rat somatosensory cortex after experimental stroke.
  • 2014
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3
  • Journal article (peer-reviewed)abstract
    • Stroke causes life long disabilities where few therapeutic options are available. Using electrical and magnetic stimulation of the brain and physical rehabilitation, recovery of brain function can be enhanced even late after stroke. Animal models support this notion, and housing rodents in an enriched environment (EE) several days after experimental stroke stimulates lost brain function by multisensory mechanisms. We studied the dynamics of functional recovery of rats with a lesion to the fore and hind limb motor areas induced by photothrombosis (PT), and with subsequent housing in either standard (STD) or EE. In this model, skilled motor function is not significantly enhanced by enriched housing, while the speed of recovery of sensori-motor function substantially improves over the 9-week study period. In particular, this stroke lesion completely obliterates the fore and hind limb placing ability when visual and whisker guidance is prevented, a deficit that persists for up to 9 weeks of recovery, but that is markedly restored within 2 weeks by enriched housing. Enriched housing after stroke also leads to a significant loss of perineuronal net (PNN) immunoreactivity; detection of aggrecan protein backbone with AB1031 antibody was decreased by 13-22%, and labelling of a glycan moiety of aggrecan with Cat-315 antibody was reduced by 25-30% in the peri-infarct area and in the somatosensory cortex, respectively. The majority of these cells are parvalbumin/GABA inhibitory interneurons that are important in sensori-information processing. We conclude that damage to the fore and hind limb motor areas provides a model of loss of limb placing response without visual guidance, a deficit also seen in more than 50% of stroke patients. This loss is amenable to recovery induced by multiple sensory stimulation and correlates with a decrease in aggrecan-containing PNNs around inhibitory interneurons. Modulating the PNN structure after ischemic damage may provide new therapies enhancing tactile/proprioceptive function after stroke.
  •  
26.
  • Madinier, Alexandre, et al. (author)
  • Impact of estrogen receptor beta activation on functional recovery after experimental stroke.
  • 2014
  • In: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 261, s. 282-288
  • Journal article (peer-reviewed)abstract
    • Acute treatment with 17β-estradiol provides effective neuroprotection during the first days after acute brain injury, however, effects of chronic activation of estrogen receptor beta (ERβ) on recovery of function after experimental stroke have not been investigated. The present study, therefore, was conducted to test if delayed treatment with the specific ERβ ligand 4-(1-phenyl-cyclohexyl)-phenol (AC-131) improves recovery of lost neurological function after permanent focal stroke induced by photothrombosis in adult Sprague-Dawley rats. Treatment was initiated on day 2 after photothrombosis and AC-131 (1, 10, and 50mg/kg) was administered by daily subcutaneous injections for 14 days. On day 2, 4, 6, 8, 11, 14, and 17 after photothrombosis, functional deficits were assessed by the paw placement test, a standardized grip strength test and an adhesive removal test. Daily treatment with AC-131 significantly improved test scores in all three behavioral tests. Importantly, improved function was not associated with a decrease in infarct volume on day 17 after stroke onset. Our results suggest that increased activity of the ERβ is involved in mechanisms of stroke recovery.
  •  
27.
  • Markus, Tina, et al. (author)
  • Neuroprotective dobutamine treatment upregulates superoxide dismutase 3, anti-oxidant and survival genes and attenuates genes mediating inflammation
  • 2018
  • In: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 19:1
  • Journal article (peer-reviewed)abstract
    • Background: Labor subjects the fetus to an hypoxic episode and concomitant adrenomodullary catecholamine surge that may provide protection against the hypoxic insult. The beta1-adrenergic agonist dobutamine protects against hypoxia/aglycemia induced neuronal damage. We aimed to identify the associated protective biological processes involved. Results: Hippocampal slices from 6 days old mice showed significant changes of gene expression comparing slices with or without dobutamine (50 mM) in the following two experimental paradigms: (1) control conditions versus lipopolysacharide (LPS) stimulation and (2) oxygen-glucose deprivation (OGD), versus combined LPS/OGD. Dobutamine depressed the inflammatory response by modifying the toll-like receptor-4 signalling pathways, including interferon regulatory factors and nuclear factor Κ B activation in experimental paradigm 1. The anti-oxidant defense genes superoxide dismutase 3 showed an upregulation in the OGD paradigm while thioredoxin reductase was upregulated in LPS paradigm. The survival genes Bag-3, Tinf2, and TMBIM-1, were up-regulated in paradigm 1. Moreover, increased levels of SOD3 were verified on the protein level 24 h after OGD and control stimulation in cultures with or without preconditioning with LPS and dobutamine, respectively. Conclusions: Neuroprotective treatment with dobutamine depresses expression of inflammatory mediators and promotes the defense against oxidative stress and depresses apoptotic genes in a model of neonatal brain hypoxia/ischemia interpreted as pharmacological preconditioning. We conclude that beta1-adrenoceptor activation might be an efficient strategy for identifying novel pharmacological targets for protection of the neonatal brain.
  •  
28.
  • Mergenthaler, Philipp, et al. (author)
  • A functional role of the cyclin-dependent kinase inhibitor 1 (p21(WAF1/CIP1)) for neuronal preconditioning
  • 2013
  • In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 33:3, s. 351-355
  • Journal article (peer-reviewed)abstract
    • Hypoxic preconditioning is thought to rely on gene products regulated by hypoxia-inducible factor (HIF)-1. Here, we show that the HIF-1 target gene cyclin-dependent kinase inhibitor 1, p21(WAF1/CIP1), is essential for neuroprotection by hypoxic/aglycemic or erythropoietin preconditioning using wild-type and p21(WAF1/CIP1)-deficient neurons. Furthermore, overexpression of wild-type p21(WAF1/CIP1) or phospho-mutants significantly increased cell death after hypoxia/aglycemia. Moreover, deferoxamine-induced endogenous tolerance did not involve p21(WAF1/CIP1) expression in cortical neurons. Our data suggest that balanced expression and potentially posttranslational regulation of p21(WAF1/CIP1) is required for hypoxic preconditioning. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 351-355; doi:10.1038/jcbfm.2012.213; published online 9 January 2013
  •  
29.
  • Michalettos, Georgios, et al. (author)
  • Crosstalk Between GABAergic Neurotransmission and Inflammatory Cascades in the Post-ischemic Brain : Relevance for Stroke Recovery
  • 2022
  • In: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 16
  • Research review (peer-reviewed)abstract
    • Adaptive plasticity processes are required involving neurons as well as non-neuronal cells to recover lost brain functions after an ischemic stroke. Recent studies show that gamma-Aminobutyric acid (GABA) has profound effects on glial and immune cell functions in addition to its inhibitory actions on neuronal circuits in the post-ischemic brain. Here, we provide an overview of how GABAergic neurotransmission changes during the first weeks after stroke and how GABA affects functions of astroglial and microglial cells as well as peripheral immune cell populations accumulating in the ischemic territory and brain regions remote to the lesion. Moreover, we will summarize recent studies providing data on the immunomodulatory actions of GABA of relevance for stroke recovery. Interestingly, the activation of GABA receptors on immune cells exerts a downregulation of detrimental anti-inflammatory cascades. Conversely, we will discuss studies addressing how specific inflammatory cascades affect GABAergic neurotransmission on the level of GABA receptor composition, GABA synthesis, and release. In particular, the chemokines CXCR4 and CX3CR1 pathways have been demonstrated to modulate receptor composition and synthesis. Together, the actual view on the interactions between GABAergic neurotransmission and inflammatory cascades points towards a specific crosstalk in the post-ischemic brain. Similar to what has been shown in experimental models, specific therapeutic modulation of GABAergic neurotransmission and inflammatory pathways may synergistically promote neuronal plasticity to enhance stroke recovery.
  •  
30.
  • Michalettos, Georgios, et al. (author)
  • Effect of Anti-inflammatory Treatment with AMD3100 and CX3CR1 Deficiency on GABAA Receptor Subunit and Expression of Glutamate Decarboxylase Isoforms After Stroke
  • 2021
  • In: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 58:11, s. 5876-5889
  • Journal article (peer-reviewed)abstract
    • Following stroke, attenuation of detrimental inflammatory pathways might be a promising strategy to improve long-term outcome. In particular, cascades driven by pro-inflammatory chemokines interact with neurotransmitter systems such as the GABAergic system. This crosstalk might be of relevance for mechanisms of neuronal plasticity, however, detailed studies are lacking. The purpose of this study was to determine if treatment with 1,1′-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] (AMD3100), an antagonist to the C-X-C chemokine receptor type 4 (CXCR4) and partial allosteric agonist to CXCR7 (AMD3100) alone or in combination with C-X3-C chemokine receptor type 1 (CX3CR1) deficiency, affect the expression of GABAA subunits and glutamate decarboxylase (GAD) isoforms. Heterozygous, CX3CR1-deficient mice and wild-type littermates were subjected to photothrombosis (PT). Treatment with AMD3100 (0.5 mg/kg twice daily i.p.) was administered starting from day 2 after induction of PT until day 14 after the insult. At this time point, GABAA receptor subunits (α3, β3, δ), GAD65 and GAD67, and CXCR4 were analyzed from the peri-infarct tissue and homotypic brain regions of the contralateral hemisphere by quantitative real-time PCR and Western Blot. Fourteen days after PT, CX3CR1 deficiency resulted in a significant decrease of the three GABAA receptor subunits in both the lesioned and the contralateral hemisphere compared to sham-operated mice. Treatment with AMD3100 promoted the down-regulation of GABAA subunits and GAD67 in the ipsilateral peri-infarct area, while the β3 subunit and the GAD isoforms were up-regulated in homotypic regions of the contralateral cortex. Changes in GABAA receptor subunits and GABA synthesis suggest that the CXCR4/7 and CX3CR1 signaling pathways are involved in the regulation of GABAergic neurotransmission in the post-ischemic brain.
  •  
31.
  • Michalettos, Georgios, et al. (author)
  • Impaired oligodendrogenesis in the white matter of aged mice following diffuse traumatic brain injury
  • 2024
  • In: GLIA. - : John Wiley & Sons. - 0894-1491 .- 1098-1136.
  • Journal article (peer-reviewed)abstract
    • Senescence is a negative prognostic factor for outcome and recovery following traumatic brain injury (TBI). TBI-induced white matter injury may be partially due to oligodendrocyte demise. We hypothesized that the regenerative capacity of oligodendrocyte precursor cells (OPCs) declines with age. To test this hypothesis, the regenerative capability of OPCs in young [(10 weeks ±2 (SD)] and aged [(62 weeks ±10 (SD)] mice was studied in mice subjected to central fluid percussion injury (cFPI), a TBI model causing widespread white matter injury. Proliferating OPCs were assessed by immunohistochemistry for the proliferating cell nuclear antigen (PCNA) marker and labeled by 5-ethynyl-2′-deoxyuridine (EdU) administered daily through intraperitoneal injections (50 mg/kg) from day 2 to day 6 after cFPI. Proliferating OPCs were quantified in the corpus callosum and external capsule on day 2 and 7 post-injury (dpi). The number of PCNA/Olig2-positive and EdU/Olig2-positive cells were increased at 2dpi (p <.01) and 7dpi (p <.01), respectively, in young mice subjected to cFPI, changes not observed in aged mice. Proliferating Olig2+/Nestin+ cells were less common (p <.05) in the white matter of brain-injured aged mice, without difference in proliferating Olig2+/PDGFRα+ cells, indicating a diminished proliferation of progenitors with different spatial origin. Following TBI, co-staining for EdU/CC1/Olig2 revealed a reduced number of newly generated mature oligodendrocytes in the white matter of aged mice when compared to the young, brain-injured mice (p <.05). We observed an age-related decline of oligodendrogenesis following experimental TBI that may contribute to the worse outcome of elderly patients following TBI.
  •  
32.
  • Ozen, Ilknur, et al. (author)
  • Interleukin-1 Beta Neutralization Attenuates Traumatic Brain Injury-Induced Microglia Activation and Neuronal Changes in the Globus Pallidus
  • 2020
  • In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:2
  • Journal article (peer-reviewed)abstract
    • Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1 beta), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1 beta was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1 beta neutralization are still poorly understood. The present study investigated the role of IL-1 beta on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1 beta neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1 beta attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.
  •  
33.
  • Quattromani, Miriana, et al. (author)
  • Enriched housing down-regulates the Toll-like receptor 2 response in the mouse brain after experimental stroke.
  • 2014
  • In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 66:Mar 6, s. 66-73
  • Journal article (peer-reviewed)abstract
    • Post-ischemic inflammation plays an important role in the evolution of brain injury, recovery and repair after stroke. Housing rodents in an enriched environment provides multisensory stimulation to the brain and enhances functional recovery after experimental stroke, also depressing the release of cytokines and chemokines in the peri-infarct. In order to identify targets for late stroke treatment, we studied the dynamics of inflammation and the contribution of resident Toll-like receptor 2 (TLR2) expressing microglia cells. We took advantage of the biophotonic/bioluminescent imaging technique using the reporter mouse-expressing luciferase and GFP reporter genes under transcriptional control of the murine TLR2 promoter (TLR2-luc/GFP mice) for non-invasive in vivo analysis of TLR2 activation/response in photothrombotic stroke after differential housing. Real-time imaging at 1day after stroke, revealed up-regulation of TLR2 in response to photothrombotic stroke that subsequently declined over time of recovery (14days). The inflammatory response was persistently down-regulated within days of enriched housing, enhancing recovery of lost sensori-motor function in TLR2-luc mice without affecting infarct size. The number of YM1-expressing microglia in the peri-infarct and areas remote from the infarct was also markedly attenuated. Using a live imaging approach, we demonstrate that multisensory stimulation rapidly, persistently and generally attenuates brain inflammation after experimental stroke, reducing the TLR2 response and leading to improved neurological outcome. TLR2-expressing microglia cells may provide targets for new stroke therapeutics.
  •  
34.
  • Quattromani, Miriana Jlenia, et al. (author)
  • Extracellular Matrix Modulation Is Driven by Experience-Dependent Plasticity During Stroke Recovery
  • 2018
  • In: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 55:3, s. 2196-2213
  • Journal article (peer-reviewed)abstract
    • Following stroke, complete cellular death in the ischemic brain area may ensue, with remaining brain areas undergoing tissue remodelling to various degrees. Experience-dependent brain plasticity exerted through an enriched environment (EE) promotes remodelling after central nervous system injury, such as stroke. Post-stroke tissue reorganization is modulated by growth inhibitory molecules differentially expressed within the ischemic hemisphere, like chondroitin sulfate proteoglycans found in perineuronal nets (PNNs). PNNs in the neocortex predominantly enwrap parvalbumin-containing GABAergic (PV/GABA) neurons, important in sensori-information processing. Here, we investigate how extracellular matrix (ECM) proteases and their inhibitors may participate in the regulation of PNN integrity during stroke recovery. Rats were subjected to photothrombotic stroke in the motor cortex, and functional deficits were assessed at 7 days of recovery. Sham and stroked rats were housed in either standard or EE conditions for 5 days, and infarct volumes were calculated. PNNs were visualized by immunohistochemistry and counted in the somatosensory cortex of both hemispheres. mRNA expression levels of ECM proteases and protease inhibitors were assessed by RT-qPCR and their activity analyzed by gel zymography. PNNs and protease activity were also studied in brains from stroke patients where similar results were observed. EE starting 2 days after stroke and continuing for 5 days stimulated behavioral recovery of limb-placement ability without affecting infarct size. EE promoted a decrease of PNNs around PV/GABA neurons and a concomitant modulation of the proteolytic activity and mRNA expression of ECM proteases and protease inhibitors in the somatosensory cortex. This study provides molecular targets for novel therapies that could support rehabilitation of stroke patients.
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35.
  • Rickhag, Mattias, et al. (author)
  • Apolipoprotein D is elevated in oligodendrocytes in the peri-infarct region after experimental stroke: influence of enriched environment.
  • 2008
  • In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 28:3, s. 551-562
  • Journal article (peer-reviewed)abstract
    • Injury to the brain (e.g., stroke) results in a disruption of neuronal connectivity and loss of fundamental sensori-motor functions. The subsequent recovery of certain functions involves structural rearrangements in areas adjacent to the infarct. This remodeling of the injured brain requires trafficking of macromolecular components including cholesterol and phospholipids, a transport carried out by apolipoproteins including apolipoprotein D (apoD). We investigated the changes in the levels of apoD mRNA and protein, and its cellular localization during a recovery period up to 30 days after experimental stroke in the rat brain. In the core of the brain infarct, apoD immunoreactivity but not mRNA increased in dying pyramidal neurons, indicative of cellular redistribution of lipids. During 2 to 7 days of recovery after stroke, the apoD levels increased in the peri-infarct and white matter areas in cells identified as mature oligodendrocytes. The apoD expressing cells were conspicuously located along the rim of the infarct, suggesting a role for apoD in tissue repair. Furthermore, housing animals in an enriched environment improved sensori-motor function and increased the apoD levels. Our data strongly suggest that apoD is involved in regenerative processes and scar formation in the peri-infarct area presumably by enhancing lipid trafficking.
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36.
  • Rudrapatna, S Umesh, et al. (author)
  • Can diffusion kurtosis imaging improve the sensitivity and specificity of detecting microstructural alterations in brain tissue chronically after experimental stroke? Comparisons with diffusion tensor imaging and histology.
  • 2014
  • In: NeuroImage. - : Elsevier BV. - 1095-9572 .- 1053-8119. ; 97:Apr 15, s. 363-373
  • Journal article (peer-reviewed)abstract
    • Imaging techniques that provide detailed insights into structural tissue changes after stroke can vitalize development of treatment strategies and diagnosis of disease. Diffusion-weighted MRI has been playing an important role in this regard. Diffusion kurtosis imaging (DKI), a recent addition to this repertoire, has opened up further possibilities in extending our knowledge about structural tissue changes related to injury as well as plasticity. In this study we sought to discern the microstructural alterations characterized by changes in diffusion tensor imaging (DTI) and DKI parameters at a chronic time point after experimental stroke. Of particular interest was the question of whether DKI parameters provide additional information in comparison to DTI parameters in understanding structural tissue changes, and if so, what their histological origins could be. Region-of-interest analysis and a data-driven approach to identify tissue abnormality were adopted to compare DTI- and DKI-based parameters in post mortem rat brain tissue, which were compared against immunohistochemistry of various cellular characteristics. The unilateral infarcted area encompassed the ventrolateral cortex and the lateral striatum. Results from region-of-interest analysis in the lesion borderzone and contralateral tissue revealed significant differences in DTI and DKI parameters between ipsi- and contralateral sensorimotor cortex, corpus callosum, internal capsule and striatum. This was reflected by a significant reduction in ipsilateral mean diffusivity (MD) and fractional anisotropy (FA) values, accompanied by significant increases in kurtosis parameters in these regions. Data-driven analysis to identify tissue abnormality revealed that the use of kurtosis-based parameters improved the detection of tissue changes in comparison with FA and MD, both in terms of dynamic range and in being able to detect changes to which DTI parameters were insensitive. This was observed in gray as well as white matter. Comparison against immunohistochemical stainings divulged no straightforward correlation between diffusion-based parameters and individual neuronal, glial or inflammatory tissue features. Our study demonstrates that DKI allows sensitive detection of structural tissue changes that reflect post-stroke tissue remodeling. However, our data also highlights the generic difficulty in unambiguously asserting specific causal relationships between tissue status and MR diffusion parameters.
  •  
37.
  • Ruscher, Karsten, et al. (author)
  • Effect of 3,4-Methylenedioxyamphetamine on Dendritic Spines Dynamics in Rat Neocortical Neurons - Involvement of Heat Shock Protein 27.
  • 2011
  • In: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1370, s. 43-52
  • Journal article (peer-reviewed)abstract
    • Along with chronic neurotoxic effects, the long-term consumption of amphetamines has been associated to psychiatric symptoms and memory disturbances. Dendritic spine dynamics have been discussed as a possible morphological correlate. However, the underlying mechanisms are still elusive. 3,4-Methylenedioxyamphetamine (MDA), a major drug of abuse and a main metabolite after 3,4-methylenedioxymethamphetamine (MDMA) intake, provokes a loss of dendritic spine like protrusions in primary cultures of rat cortical neurons. 3,4-Methylenedioxyamphetamine also induced a rapid activation of the p38 mitogen activated protein kinase (p38 MAPK) pathway and phosphorylation of heat shock protein 27 (hsp27) indicative for its decreased chaperone activity. Concurrent pharmacological inhibition of the p38 MAPK by SB203580 abolished hsp27 phosphorylation and diminished the loss of dendritic spine-like protrusions. Moreover, upon MDA treatment dendritic spine-like protrusions were stabilized in neurons constitutively expressing hsp27. In parallel experiments we observed a robust activation of the heat shock transcription factor 1 (HSF-1) and a subsequent increase of hsp27 and hsp70. The regulation of small heat shock proteins corroborates the existence of a neuronal stress response after MDA treatment. Pharmacological targeting of small heat shock protein phosphorylation may provide a new strategy to preserve spine integrity after amphetamine exposure.
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38.
  • Ruscher, Karsten, et al. (author)
  • Effects of chronic clozapine administration on apolipoprotein D levels and on functional recovery following experimental stroke.
  • 2010
  • In: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1321, s. 152-163
  • Journal article (peer-reviewed)abstract
    • Elevated brain levels of apolipoprotein D (ApoD) correlate with improved neurological recovery after experimental stroke. Hence, a pharmacological induction of ApoD in the postischemic brain could be beneficial for recovery after stroke. Here we investigated the effect of Clozapine, a compound that increases the expression of ApoD, in two rat models of experimental stroke. Rats were subjected to permanent occlusion of the middle cerebral artery (pMCAO) and treated with Clozapine (i.p. 10mg/kg body weight) or saline for 8 or 28days starting on the second day after MCAO. ApoD levels increased by 35% in the peri-infarct area after 10 and 30days after pMCAO, mainly in neuron-specific nuclear protein (NeuN) positive neurons and glial fibrillary acidic protein (GFAP) positive astrocytes. Clozapine did not affect the neurological deficit assessed by the rotating pole test and a grip strength test at 7d, 14d, 21d, and 28days after pMCAO. Functional outcome and the infarct size were similar in rats subjected to transient MCAO and injected with Clozapine (i.p. 10mg/kg body weight) or saline for 26days starting on the second day after tMCAO. We conclude that Clozapine affects cellular processes involved in peri-infarct tissue reorganization, but does not affect functional recovery after MCAO.
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39.
  • Ruscher, Karsten, et al. (author)
  • Effects of the sigma-1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydro-chloride on inflammation after stroke.
  • 2012
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:9
  • Journal article (peer-reviewed)abstract
    • Activation of the sigma-1 receptor (Sig-1R) improves functional recovery in models of experimental stroke and is known to modulate microglia function. The present study was conducted to investigate if Sig-1R activation after experimental stroke affects mediators of the inflammatory response in the ischemic hemisphere. Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (MCAO) and injected with the specific Sig-1R agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) or saline for 5 days starting on day 2 after MCAO. Treatment did not affect the increased levels of the pro-inflammatory cytokines interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13) in the infarct core and peri-infarct area after MCAO. In addition, treatment with SA4503 did not affect elevated levels of nitrite, TNF-α and IL-1β observed in primary cultures of microglia exposed to combined Hypoxia/Aglycemia, while the unspecific sigma receptor ligand 1,3-di-o-tolylguanidine (DTG) significantly decreased the production of nitrite and levels of TNF-α. Analysis of the ischemic hemisphere also revealed increased levels of ionized calcium binding adaptor molecule 1 (Iba1) levels in the infarct core of SA4503 treated animals. However, no difference in Iba1 immunoreactivity was detected in the infarct core. Also, levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and OX-42 were not increased in the infarct core in rats treated with SA4503. Together, our results suggest that sigma-1 receptor activation affects Iba1 expression in microglia/macrophages of the ischemic hemisphere after experimental stroke but does not affect post-stroke inflammatory mediators.
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40.
  • Ruscher, Karsten, et al. (author)
  • Enriched environment reduces apolipoprotein E (ApoE) in reactive astrocytes and attenuates inflammation of the peri-infarct tissue after experimental stroke.
  • 2009
  • In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 29, s. 1796-1805
  • Journal article (peer-reviewed)abstract
    • Apolipoprotein E (ApoE), a cholesterol transporter and an immunomodulator, is brain protective after experimental stroke and implicated in brain repair. Here, we study the involvement of ApoE in the restoration of brain function after experimental stroke, by using animal housing conditions that differentially improve recovery after occlusion of the middle cerebral artery occlusion (MCAO). We found that after MCAO the ApoE levels increased in the injured hemisphere over a 30 days recovery period. The exception was a proximal narrow peri-infarct rim, in which ApoE was solely localized in S100beta(+)/glial fibrillary acidic protein (GFAP) negative reactive astrocytes at 4 to 7 days of recovery. Enriched housing after MCAO caused a marked decrease in ApoE levels compared with standard housing conditions, particularly in the ApoE/S100beta(+) reactive astrocytes. In addition, the levels of interleukin 1beta were lower in animals housed in an enriched environment. We propose that during the subacute phase after experimental stroke a zone for tissue reorganization with low cellular ApoE levels is formed. We conclude that the strong sensori-motor stimulation provided by enriched housing conditions mitigates the inflammatory response after stroke decreasing the level of ApoE that may contribute to the observed improvement of functional recovery.Journal of Cerebral Blood Flow & Metabolism advance online publication 22 July 2009; doi:10.1038/jcbfm.2009.96.
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41.
  • Ruscher, Karsten, et al. (author)
  • Housing in an enriched environment : A tool to study functional recovery after experimental stroke
  • 2016. - 2nd
  • In: Rodent Models of Stroke. - New York, NY : Springer New York. - 1940-6045 .- 0893-2336. - 9781493956203 - 9781493956180 ; 120, s. 85-92
  • Book chapter (peer-reviewed)abstract
    • Physical therapy and social interactions between the stroke patient and health-care professionals or relatives facilitate the process of recovery and promote improvement of lost neurological function after stroke. These observations can be mimicked in an experimental setting by multimodal stimulation provided in the concept of enriched environment. The enriched environment is a housing condition for rodents combining social interactions and sensorimotor stimulation that improves lost neurological function without affecting the extent of brain damage after experimental stroke. This chapter deals with the concept of enriched housing and about performing studies using enriched environment as tool to investigate mechanisms of recovery after brain injury.
  •  
42.
  • Ruscher, Karsten, et al. (author)
  • Housing in an enriched environment : A tool to study functional recovery after experimental stroke
  • 2010
  • In: Rodent Models of Stroke. - Totowa, NJ : Humana Press. - 1940-6045 .- 0893-2336. - 9781607617495 - 9781607617501 ; 47, s. 85-91
  • Book chapter (peer-reviewed)abstract
    • Physical therapy and social interactions between the stroke patient and health care professionals or relatives facilitate the process of recovery and promote the improvement of neurological function after stroke. These observations can be mimicked in the experimental setting with the concept of enriched environment. The enriched environment is a housing condition for rodents combining social interactions and sensorimotor stimulation that improves neurological function without affecting the extent of brain damage after experimental stroke. This chapter deals with the concept of enriched housing and performing studies using enriched environment as a tool to investigate mechanisms of recovery after brain injury.
  •  
43.
  • Ruscher, Karsten, et al. (author)
  • Inhibition of CXCL12 signaling attenuates the postischemic immune response and improves functional recovery after stroke.
  • 2013
  • In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 33:8, s. 1225-1234
  • Journal article (peer-reviewed)abstract
    • After stroke, brain inflammation in the ischemic hemisphere hampers brain tissue reorganization and functional recovery. Housing rats in an enriched environment (EE) dramatically improves recovery of lost neurologic functions after experimental stroke. We show here that rats housed in EE after stroke induced by permanent occlusion of the middle cerebral artery (pMCAO), showed attenuated levels of proinflammatory cytokines in the ischemic core and the surrounding peri-infarct area, including a significant reduction in the stroke-induced chemokine receptor CXCR4 and its natural ligand stromal cell-derived factor-1 (CXCL12). To mimic beneficial effects of EE, we studied the impact of inhibiting CXCL12 action on functional recovery after transient MCAO (tMCAO). Rats treated with the specific CXCL12 receptor antagonist 1-[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclo-tetradecan (AMD3100) showed improved recovery compared with saline-treated rats after tMCAO, without a concomitant reduction in infarct size. This was accompanied by a reduction of infiltrating immune cells in the ischemic hemisphere, particularly cluster of differentiation 3-positive (CD3(+)) and CD3(+)/CD4(+) T cells. Spleen atrophy and delayed death of splenocytes, induced by tMCAO, was prevented by AMD3100 treatment. We conclude that immoderate excessive activation of the CXCL12 pathway after stroke contributes to depression of neurologic function after stroke and that CXCR4 antagonism is beneficial for the recovery after stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 1 May 2013; doi:10.1038/jcbfm.2013.71.
  •  
44.
  • Ruscher, Karsten, et al. (author)
  • Levodopa Treatment Improves Functional Recovery After Experimental Stroke.
  • 2012
  • In: Stroke: a journal of cerebral circulation. - 1524-4628. ; 43, s. 507-513
  • Journal article (peer-reviewed)abstract
    • BACKGROUND AND PURPOSE: Delayed treatment of patients with stroke with levodopa/benserazide contributes to enhanced functional recovery, but the mechanisms involved are poorly understood. The present study was designed to investigate if levodopa/benserazide treatment improves recovery of lost neurological function and contributes to tissue reorganization in the rat brain after stroke. METHODS: Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (120 minutes) and treated with levodopa (1, 5, and 20 mg/kg)/benserazide (15 mg/kg) or saline for 12 consecutive days starting on Day 2 after transient occlusion of the middle cerebral artery. Infarct volume was determined and sensorimotor function was assessed using the rotating pole test, a 28-point neuroscore, and a cylinder test on Days 2, 7, and 14 after transient occlusion of the middle cerebral artery. The spatiotemporal expression pattern of dopamine-1 and dopamine-2 receptors and the dopamine- and cAMP-regulated neuronal phosphoprotein in reactive astrocytes were analyzed in the ischemic hemisphere as well as in cultured astrocytes. RESULTS: Treatment with levodopa/benserazide significantly improved the recovery of sensorimotor function after transient occlusion of the middle cerebral artery without affecting the infarct volume. In addition, we found that different subpopulations of glial fibrillary acidic protein-positive astrocytes in the peri-infarct area express dopamine-1 receptors and dopamine-2 receptors as well as dopamine- and cAMP-regulated neuronal phosphoprotein. CONCLUSIONS: Our results strongly corroborate the concept of recovery enhancing actions of levodopa treatment after stroke. Also, astrocytes in the peri-infarct area may contribute to the dopamine enhanced recovery mechanisms.
  •  
45.
  • Ruscher, Karsten, et al. (author)
  • Neuroprotective effects of the beta-carboline abecarnil studied in cultured cortical neurons and organotypic retinal cultures.
  • 2007
  • In: Neuropharmacology. - : Elsevier BV. - 1873-7064 .- 0028-3908. ; 52:7, s. 1488-1495
  • Journal article (peer-reviewed)abstract
    • Presently there is no neuroprotective pharmacological treatment of proven clinical safety and efficacy available. The purpose of this study was to investigate whether the ss-carboline, abecarnil (Abe), which has already passed clinical phase III trials in patients with anxiety disorders, is neuroprotective in in vitro models of cerebral ischemia or excitotoxicity. Abe (100 nM) protected cultured cortical neurons when applied 20 min before or 20 min after combined oxygen glucose deprivation (OGD). Furthermore, cultured cortical neurons were protected from NMDA excitotoxicity when Abe (100 nM) was administered 20 min before or concurrent with 100 mu M NMDA. In contrast, in adult rat organotypic retinal cultures, Abe failed to protect retinal ganglion cells (RGCs) against glutamate (Glu) excitotoxicity. Thus, although our data demonstrate that Abe is a potential neuroprotectant in cultured neurons, the lack of effect in an organotypical model of Glu toxicity indicates that further study is required before Abe might be considered for human neuroprotection trials. 2007 Elsevier Ltd. All rights reserved.
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46.
  •  
47.
  • Ruscher, Karsten, et al. (author)
  • The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration.
  • 2015
  • In: Journal of Pharmacological Sciences. - : Elsevier BV. - 1347-8648 .- 1347-8613. ; 127:1, s. 30-35
  • Research review (peer-reviewed)abstract
    • The sigma-1 receptor (Sig-1R) is a single 25 kD polypeptide and a chaperone protein immersed in lipid rafts of the endoplasmic reticulum (ER) where it interacts with mitochondria at the mitochondria-associated ER membrane domain (MAM). Upon activation, the Sig-1R binds to the inositol trisphosphate receptor (IP3R), and modulates cellular calcium (Ca(2+)) homeostasis. Also, the activated Sig-1R modulates plasma membrane receptor and ion channel functions, and may regulate cellular excitability. Further, the Sig-1R promotes trafficking of lipids and proteins essential for neurotransmission, cell growth and motility. Activation of the Sig-1R provides neuroprotection and is neurorestorative in cellular and animal models of neurodegenerative diseases and brain ischaemia. Neuroprotection appears to be due to inhibition of cellular Ca(2+) toxicity and/or inflammation, and neurorestoration may include balancing abberant neurotransmission or stimulation of synaptogenesis, thus remodelling brain connectivity. Single nucleotide polymorphisms and mutations of the SIGMAR1 gene worsen outcome in Alzheimer's disease and myotrophic lateral sclerosis supporting a role of Sig-1R in neurodegenerative disease. The combined neuroprotective and neurorestorative actions of the Sig-1R, provide a broad therapeutic time window of Sig-1R agonists. The Sig-1R is therefore a strong therapeutic target for the development of new treatments for neurodegenerative diseases and stroke.
  •  
48.
  • Ruscher, Karsten, et al. (author)
  • The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke.
  • 2011
  • In: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 134:3, s. 732-746
  • Journal article (peer-reviewed)abstract
    • Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in an enriched environment for two weeks after permanent middle cerebral artery occlusion, we found increased sigma-1 receptor expression in peri-infarct areas. Treatment of rats subjected to permanent or transient middle cerebral artery occlusion with 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor activation increased the levels of the synaptic protein neurabin and neurexin in membrane rafts in the peri-infarct area, while sigma-1 receptor silencing prevented sigma-1 receptor-mediated neurite outgrowth in primary cortical neuronal cultures. In astrocytic cultures, oxygen and glucose deprivation induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma-1 receptor activation stimulates recovery after stroke by enhancing cellular transport of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection.
  •  
49.
  • Saraiva, Cláudia, et al. (author)
  • MicroRNA-124-loaded nanoparticles increase survival and neuronal differentiation of neural stem cells in vitro but do not contribute to stroke outcome in vivo
  • 2018
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
  • Journal article (peer-reviewed)abstract
    • There is a high quest for novel therapeutic strategies to enhance recovery after stroke. MicroRNA-124 (miR-124) has been described as neuroprotective and anti-inflammatory molecule. Moreover, miR-124 is a well described enhancer of adult neurogenesis that could offer potentially beneficial effects. Herein, we used miR-124-loaded nanoparticles (miR-124 NPs) to evaluate their therapeutic potential in an in vitro and in vivo model of stroke. For that, neuroprotective and neurogenic responses were assessed in an in vitro model of stroke. Here, we found that miR-124 NPs decreased cell death and improved neuronal differentiation of subventricular zone (SVZ) neural stem cell cultures after oxygen and glucose deprivation. In contrast, intravenous injection of miR-124 NPs immediately after permanent focal ischemia induced by photothrombosis (PT) did not provide a better neurological outcome. In addition, treatment did not affect the number of 5-bromo-2’-deoxyuridine (BrdU)- and doublecortin/BrdU- positive cells in the SVZ at the study endpoint of 14 days after PT. Likewise, the ischemic insult did not affect the numbers of neuronal progenitors in the SVZ. However, in PT mice miR-124 NPs were able to specifically augment interleukin-6 levels at day 2 post-stroke. Furthermore, we also showed that NPs reached the brain parenchyma and were internalized by brain resident cells. Although, promising in vitro data could not be verified in vivo as miR-124 NPs treatment did not improve functional outcome nor presented beneficial actions on neurogenesis or post-stroke inflammation, we showed that our NP formulation can be a safe alternative for drug delivery into the brain.
  •  
50.
  • Talhada, Daniela, et al. (author)
  • Performing Enriched Environment Studies to Improve Functional Recovery
  • 2023
  • In: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer US. - 1940-6029. ; 2616, s. 355-366
  • Journal article (peer-reviewed)abstract
    • Physical therapy and social interactions between the stroke patient and healthcare professionals or relatives facilitate the process of recovery and promote improvement of lost neurological function after stroke. These observations can be mimicked in an experimental setting by multimodal stimulation provided in the concept of enriched environment. The enriched environment is a housing condition combining social interactions and sensorimotor stimulation that improves lost neurological function without affecting the extent of brain damage after experimental stroke. This chapter provides a detailed protocol on how to perform enriched housing experiments including conceptual and technical considerations as a tool to investigate mechanisms of recovery after brain injury.
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