| 1. |
- Deshpande, J, et al.
(författare)
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Ultrastructural changes in the hippocampal CA1 region following transient cerebral ischemia: evidence against programmed cell death.
- 1992
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Ingår i: Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. - 0014-4819. ; 88:1, s. 91-105
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Tidskriftsartikel (refereegranskat)abstract
- The ultrastructural changes in the pyramidal neurons of the CA1 region of the hippocampus were studied 6 h, 24 h, 48 h, and 72 h following a transient 10 min period of cerebral ischemia induced by common carotid occlusion combined with hypotension. The pyramidal neurons showed delayed neuronal death (DND), i.e. at 24 h and 48 h postischemia few structural alterations were noted in the light microscope, while at 72 h extensive neuronal degeneration was apparent. The most prominent early ultrastructural changes were polysome disaggregation, and the appearance of electron-dense fluffy dark material associated with tubular saccules. Mitochondria and nuclear elements appeared intact until frank neuronal degeneration. The dark material accumulated with extended periods of recirculation in soma and in the main trunks of proximal dendrites, often beneath the plasma membrane, less frequently in the distal dendrites and seldom in spines. Protein synthesis inhibitors (anisomycin, cycloheximide) and an RNA synthesis inhibitor (actinomycin D), administered by intrahippocampal injections or subcutaneously, did not mitigate neuronal damage. Therefore, DND is probably not apoptosis or a form of programmed cell death. We propose that the dark material accumulating in the postischemic period represents protein complexes, possibly aggregates of proteins or internalized plasma membrane fragments, which may disrupt vital cellular structure and functions, leading to cell death.
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| 2. |
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| 3. |
- Francardo, Veronica, et al.
(författare)
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Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism
- 2014
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137, s. 1998-2014
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Quattromani, Miriana Jlenia, et al.
(författare)
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Extracellular Matrix Modulation Is Driven by Experience-Dependent Plasticity During Stroke Recovery
- 2018
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Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 55:3, s. 2196-2213
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Macleod, Malcolm R, et al.
(författare)
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Mineralocorticoid receptor expression and increased survival following neuronal injury
- 2003
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 17:8, s. 1549-1555
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids, acting via the mineralocorticoid receptor, are required for granule neuronal survival in the rat dentate gyrus. Whether this mineralocorticoid receptor-mediated neuroprotective effect has more general applicability is unknown. Here we report increased mineralocorticoid receptor expression in rat hippocampal and cortical neurons exposed in vitro to low levels of staurosporine and in rat hippocampal pyramidal neurons exposed in vivo to hypothermic transient global ischaemia. In both the cell culture system and the in vivo system increased mineralocorticoid receptor expression is associated with increased neuronal survival, and this increase is reversed by mineralocorticoid receptor antagonism. Modulation of mineralocorticoid receptor gene expression may therefore be an important target for reduction of brain injury in conditions caused by cerebral ischaemia including brain damage following cardiac arrest and stroke.
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| 6. |
- Lobo, Andrea C., et al.
(författare)
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Cleavage of the vesicular glutamate transporters under excitotoxic conditions
- 2011
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 44:3, s. 292-303
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Tidskriftsartikel (refereegranskat)abstract
- Glutamate is loaded into synaptic vesicles by vesicular glutamate transporters (VGLUTs), and alterations in the transporters expression directly regulate neurotransmitter release. We investigated changes in VGLUT1 and VGLUT2 protein levels after ischemic and excitotoxic insults. The results show that VGLUT2 is cleaved by calpains after excitotoxic stimulation of hippocampal neurons with glutamate, whereas VGLUT1 is downregulated to a lower extent VGLUT2 was also cleaved by calpains after oxygen/glucose deprivation (OGD), and downregulated after middle cerebral artery occlusion (MCAO) and intrahippocampal injection of kainate. In contrast, VGLUT1 was not affected after OGD. Incubation of isolated synaptic vesicles with recombinant calpain also induced VGLUT2 cleavage, with a little effect observed for VGLUT1. N-terminal sequencing analysis showed that calpain cleaves VGLUT2 in the C-terminus, at Asn(534) and Lys(542). The truncated GFP-VGWT2 forms were found to a great extent in non-synaptic regions along neurites, when compared to GFP-VGLUT2. These findings show that excitotoxic and ischemic insults downregulate VGLUT2, which is likely to affect glutamatergic transmission and cell death, especially in the neonatal period when the transporter is expressed at higher levels. (C) 2011 Elsevier Inc. All rights reserved.
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| 7. |
- Hougaard, Kjeld, et al.
(författare)
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Cerebral metabolic and circulatory effects of 1,1,1-trichloroethane, a neurotoxic industrial solvent - 1. Effects on local cerebral glucose consumption and blood flow during acute exposure
- 1984
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Ingår i: Neurochemical Pathology. - 0734-600X. ; 2:1, s. 39-53
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Tidskriftsartikel (refereegranskat)abstract
- The effects of inhaled 1,1,1-trichloroethane (3500, 6000, and 7800 ppm) on behavior, local cerebral blood flow, and local cerebral glucose consumption were studied in awake rats. The effect of the solvent inhalation on the EEG pattern and local cerebral blood flow was also studied in paralyzed animals under N2O analgesia. Exposure of awake animals to 6000 ppm 1,1,1-trichloroethane induced a decrease in motility and exploratory behavior. At 7800 ppm the rats were clearly ataxic. The local cerebral glucose consumption in 23 brain regions was studied by the [14C]deoxyglucose technique. A decrease was observed ranging from 14 to 55% of control values. The inferior colliculus and substantia nigra displayed the largest reductions. In exposed animals the local cerebral blood flow increased in 11 brain structures by 28-45%. In animals under N2O analgesia, 7400 ppm 1,1,1-trichloroethane induced a depression of the EEG activity. In these animals the local cerebral blood flow increased by 12-99%, with a large variability in blood flow between the different structures. It is concluded that exposure of rats to subanesthetic doses of 1,1,1-trichloroethane induces an increase in cerebral blood flow in spite of a concomitant decrease in glucose consumption and depression of cerebral function.
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| 8. |
- Anderson, Kevin J., et al.
(författare)
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Ischemia-induced upregulation of excitatory amino acid transport sites
- 1993
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Ingår i: Brain Research. - 0006-8993. ; 622:1-2, s. 93-98
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Tidskriftsartikel (refereegranskat)abstract
- The response of excitatory amino acid transporter binding sites in the rat brain to 10 min of cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension was examined. We observed a transient increase in the density of transporter binding sites that was first noticeable at 5 min post-recovery and persisted for 48 h. The increase in binding sites was found throughout the brain, but was most prevalent in hippocampus and other cortical regions. We conclude that delayed neuronal death following transient cerebral ischemia may not be due to a decrease in the number of excitatory amino acid transport sites.
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| 9. |
- Bergstedt, Kerstin, et al.
(författare)
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Initiation of protein synthesis and heat-shock protein-72 expression in the rat brain following severe insulin-induced hypoglycemia
- 1993
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Ingår i: Acta Neuropathologica. - 0001-6322. ; 86:2, s. 145-153
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Tidskriftsartikel (refereegranskat)abstract
- Following stress such as heat shock or transient cerebral ischemia, global brain protein synthesis initiation is depressed through modulation of eucaryotic initiation factor (eIF) activities, and modification of ribosomal subunits. Concomitantly, expression of a certain class of mRNA, heat-shock protein (HSP) mRNA, is induced. Here we report that the activity of eucaryotic initiation factor-2 (eIF-2), a protein that participates in the regulation of a rate-limiting initiation step of protein synthesis, transiently decreases following insulin-induced severe hypoglycemia in the rat brain neocortex. Expression of HSP 72, a 72-kDa HSP, in surviving neurons was seen at 1-7 days of recovery following 30 min of hypoglycemic coma, but not at 1 h and 6 h of recovery. In the neocortex, HSP 72 was first seen in layer IV, and later also in surviving neurons in layer II. In the CA1 region and in the crest of dentate gyrus, HSP 72 expression was evident in cells adjacent to irreversibly damaged neurons. In the CA3 region and the hilus of dentate gyrus, HSP 72 was expressed in a few scattered neurons. In septal nucleus, HSP 72 was expressed in a lateral to medial fashion over a period of 1-3 days of recovery. We conclude that severe insulin-induced hypoglycemia induces a stress response in neurons in the recovery phase, including inhibition of protein synthesis initiation, depression of eIF-2 activity, and a delayed and prolonged expression of HSP 72 in surviving neurons. The HSP 72 expression may be a protective response to injurious stress.
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| 10. |
- Bergstedt, Kerstin, et al.
(författare)
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Postischaemic changes in protein synthesis in the rat brain : effects of hypothermia
- 1993
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Ingår i: Experimental Brain Research. - 0014-4819. ; 95:1, s. 91-99
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Tidskriftsartikel (refereegranskat)abstract
- Protein synthesis, measured as [14C]-leucine incorporation into proteins, was studied in the normothermic rat brain following 15 min of transient cerebral ischaemia and 1 h, 24 h and 48 h of recirculation, and in the hypothermic (33°C) brain following 1 h and 48 h of recirculation. Ischaemia was induced by bilateral common carotid occlusion combined with hypotension. Following normothermic ischaemia, incorporation of [14C]-leucine was depressed by 40-80% at 1 h of recirculation in all brain regions studied. At 48 h postischaemia, incorporation returned to normal or above normal levels in the inner layers of neocortex, the CA3 region, the striatum and the dentate gyrus, while in the outer layers of neocortex and in the hippocampal CA1 region the incorporation was persistently decreased by 26% and 40% respectively. At 24 and 48 h postischaemia, protein synthesis in the CA1 region and the striatum could be attributed to proliferating microglia. Intra-ischaemic hypothermia ameliorated the persistent depression of protein synthesis in the CA1 region at 48 h postischaemia, and a two-fold increase compared to the normothermic group was observed both in the CA1 region and the striatum. In the cortex, eucaryotic initiation factor 2 activity transiently decreased at 30 min postischaemia. In animals subjected to intra-ischaemic hypothermia, the eucaryotic initiation factor 2 activity was reduced by 50% of control at 30 min of recirculation compared with 77% in normothermic animals. We conclude that the postischaemic depression of protein synthesis is in part caused by a decrease in eucaryotic initiation factor 2 activity. The early postischaemic depression may reflect a reaction of the tissue to stress, while the late persistent depression, which is normalised by intra-ischaemic hypothermia, may be related to the mechanism of cell death.
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