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- Krassnitzer, M, et al.
(författare)
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Resident Astrocytes can Limit Injury to Developing Hippocampal Neurons upon THC Exposure
- 2023
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Ingår i: Neurochemical research. - : Springer Science and Business Media LLC. - 1573-6903 .- 0364-3190. ; 48:4, s. 1242-1253
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Tidskriftsartikel (refereegranskat)abstract
- Cannabis legalization prompted the dilemma if plant-derived recreational drugs can have therapeutic potential and, consequently, how to address their regulation and safe distribution. In parallel, the steady worldwide decriminalization of cannabis and the enhanced content of its main psychoactive compound Δ9-tetrahydrocannabinol (THC), exposes populations to increasing amounts of cannabis and THC across all ages. While adverse effects of cannabis during critical stages of fetal neurodevelopment are investigated, these studies center on neurons alone. Thus, a gap of knowledge exists on how intercellular interactions between neighboring cell types, particularly astrocytes and neurons, could modify THC action. Here, we combine transcriptome analysis, transgenic models, high resolution microscopy and live cell imaging to demonstrate that hippocampal astrocytes accumulate in the strata radiatum and lacunosum moleculare of the CA1 subfield, containing particularly sensitive neurons to stressors, upon long term postnatal THC exposure in vivo. As this altered distribution is not dependent on cell proliferation, we propose that resident astrocytes accumulate in select areas to protect pyramidal neurons and their neurite extensions from pathological damage. Indeed, we could recapitulate the neuroprotective effect of astrocytes in vitro, as their physical presence significantly reduced the death of primary hippocampal neurons upon THC exposure (> 5 µM). Even so, astrocytes are also affected by a reduced metabolic readiness to stressors, as reflected by a downregulation of mitochondrial proteins. Thus, we find that astrocytes exert protective functions on local neurons during THC exposure, even though their mitochondrial electron transport chain is disrupted.
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- Mahawar, Lovely, et al.
(författare)
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Iron deficiency in plants : an update on homeostasis and its regulation by nitric oxide and phytohormones
- 2023
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Ingår i: Plant growth regulation (Print). - : Springer. - 0167-6903 .- 1573-5087. ; 100, s. 283-299
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Forskningsöversikt (refereegranskat)abstract
- Iron is an essential micronutrient for plants as it involves in several important physiological processes. Understanding iron homeostasis in plants is pivotal, not only for improving their growth and development but also for enhancing human nutrition as plants are the principal dietary source of iron. This calls for the need to enrich bioavailable iron in crops to resolve iron starvation issue especially in low income and rural populations who have limited access to food markets and proper health facilities. The uptake of iron from rhizosphere, its transporters and transcription factors that regulate iron acquisition are well characterized. Here, the present review emphasizes on the role of signalling molecules particularly phytohormones and nitric oxide and their interactive co-ordination in iron homeostasis in agriculturally important crops that grow at pH 6.0-7.5 and have limited access to Fe2+. The involvement of these signalling molecules in up-regulating iron acquisition genes (FRO2 and IRT1), iron translocation to the cellular compartments and accessibility of iron storage which are important for proper iron homeostasis hence can be considered as vital biofortification strategy for crop plants to address hidden hunger.
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- Pekna, Marcela, 1966, et al.
(författare)
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Astrocyte Responses to Complement Peptide C3a are Highly Context-Dependent
- 2023
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Ingår i: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 48:4, s. 1233-1241
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Tidskriftsartikel (refereegranskat)abstract
- Astrocytes perform a range of homeostatic and regulatory tasks that are critical for normal functioning of the central nervous system. In response to an injury or disease, astrocytes undergo a pronounced transformation into a reactive state that involves changes in the expression of many genes and dramatically changes astrocyte morphology and functions. This astrocyte reactivity is highly dependent on the initiating insult and pathological context. C3a is a peptide generated by the proteolytic cleavage of the third complement component. C3a has been shown to exert neuroprotective effects, stimulate neural plasticity and promote astrocyte survival but can also contribute to synapse loss, Alzheimer's disease type neurodegeneration and blood-brain barrier dysfunction. To test the hypothesis that C3a elicits differential effects on astrocytes depending on their reactivity state, we measured the expression of Gfap, Nes, C3ar1, C3, Ngf, Tnf and Il1b in primary mouse cortical astrocytes after chemical ischemia, after exposure to lipopolysaccharide (LPS) as well as in control naive astrocytes. We found that C3a down-regulated the expression of Gfap, C3 and Nes in astrocytes after ischemia. Further, C3a increased the expression of Tnf and Il1b in naive astrocytes and the expression of Nes in astrocytes exposed to LPS but did not affect the expression of C3ar1 or Ngf. Jointly, these results provide the first evidence that the complement peptide C3a modulates the responses of astrocytes in a highly context-dependent manner.
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- Pekna, Marcela, 1966, et al.
(författare)
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Targeting Complement C3a Receptor to Improve Outcome After Ischemic Brain Injury
- 2021
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Ingår i: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 46, s. 2626-2637
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Tidskriftsartikel (refereegranskat)abstract
- Ischemic stroke is a major cause of disability. No efficient therapy is currently available, except for the removal of the occluding blood clot during the first hours after symptom onset. Loss of function after stroke is due to cell death in the infarcted tissue, cell dysfunction in the peri-infarct region, as well as dysfunction and neurodegeneration in remote brain areas. Plasticity responses in spared brain regions are a major contributor to functional recovery, while secondary neurodegeneration in remote regions is associated with depression and impedes the long-term outcome after stroke. Hypoxic-ischemic encephalopathy due to birth asphyxia is the leading cause of neurological disability resulting from birth complications. Despite major progress in neonatal care, approximately 50% of survivors develop complications such as mental retardation, cerebral palsy or epilepsy. The C3a receptor (C3aR) is expressed by many cell types including neurons and glia. While there is a body of evidence for its deleterious effects in the acute phase after ischemic injury to the adult brain, C3aR signaling contributes to better outcome in the post-acute and chronic phase after ischemic stroke in adults and in the ischemic immature brain. Here we discuss recent insights into the novel roles of C3aR signaling in the ischemic brain with focus on the therapeutic opportunities of modulating C3aR activity to improve the outcome after ischemic stroke and birth asphyxia.
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- Sharma, Hari Shanker, et al.
(författare)
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Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50-60 nm) Nanoparticles
- 2023
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Ingår i: Neurochemical Research. - : Springer Nature. - 0364-3190 .- 1573-6903. ; 48, s. 1864-1888
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Tidskriftsartikel (refereegranskat)abstract
- Neuropathic pain is associated with abnormal sensations and/or pain induced by non-painful stimuli, i.e., allodynia causing burning or cold sensation, pinching of pins and needles like feeling, numbness, aching or itching. However, no suitable therapy exists to treat these pain syndromes. Our laboratory explored novel potential therapeutic strategies using a suitable composition of neurotrophic factors and active peptide fragments-Cerebrolysin (Ever Neuro Pharma, Austria) in alleviating neuropathic pain induced spinal cord pathology in a rat model. Neuropathic pain was produced by constrictions of L-5 spinal sensory nerves for 2-10 weeks period. In one group of rats cerebrolysin (2.5 or 5 ml/kg, i.v.) was administered once daily after 2 weeks until sacrifice (4, 8 and 10 weeks). Ag, Cu and Al NPs (50 mg/kg, i.p.) were delivered once daily for 1 week. Pain assessment using mechanical (Von Frey) or thermal (Hot-Plate) nociceptive showed hyperalgesia from 2 weeks until 10 weeks progressively that was exacerbated following Ag, Cu and Al NPs intoxication in nerve lesioned groups. Leakage of Evans blue and radioiodine across the blood-spinal cord barrier (BSCB) is seen from 4 to 10 weeks in the rostral and caudal cord segments associated with edema formation and cell injury. Immunohistochemistry of albumin and GFAP exhibited a close parallelism with BSCB leakage that was aggravated by NPs following nerve lesion. Light microscopy using Nissl stain exhibited profound neuronal damages in the cord. Transmission electron microcopy (TEM) show myelin vesiculation and synaptic damages in the cord that were exacerbated following NPs intoxication. Using ELISA spinal tissue exhibited increased albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and heat shock protein (HSP 72kD) upregulation together with cytokines TNF-alpha, IL-4, IL-6, IL-10 levels in nerve lesion that was exacerbated following NPs intoxication. Cerebrolysin treatment significantly reduced hyperalgesia and attenuated BSCB disruption, edema formation and cellular changes in nerve lesioned group. The levels of cytokines were also restored near normal levels with cerebrolysin treatment. Albumin, GFAP, MABP and HSP were also reduced in cerebrolysin treated group and thwarted neuronal damages, myelin vesiculation and cell injuries. These neuroprotective effects of cerebrolysin with higher doses were also effective in nerve lesioned rats with NPs intoxication. These observations suggest that cerebrolysin actively protects spinal cord pathology and hyperalgesia following nerve lesion and its exacerbation with metal NPs, not reported earlier.
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- Skoug, Cecilia, et al.
(författare)
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Sphingosine 1-Phoshpate Receptors are Located in Synapses and Control Spontaneous Activity of Mouse Neurons in Culture
- 2022
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Ingår i: Neurochemical Research. - : Springer Science and Business Media LLC. - 1573-6903 .- 0364-3190. ; 47:10, s. 3114-3125
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Tidskriftsartikel (refereegranskat)abstract
- Sphingosine-1-phosphate (S1P) is best known for its roles as vascular and immune regulator. Besides, it is also present in the central nervous system (CNS) where it can act as neuromodulator via five S1P receptors (S1PRs), and thus control neurotransmitter release. The distribution of S1PRs in the active zone and postsynaptic density of CNS synapses remains unknown. In the current study, we investigated the localization of S1PR1-5 in synapses of the mouse cortex. Cortical nerve terminals purified in a sucrose gradient were endowed with all five S1PRs. Further subcellular fractionation of cortical nerve terminals revealed S1PR2 and S1PR4 immunoreactivity in the active zone of presynaptic nerve terminals. Interestingly, only S1PR2 and S1PR3 immunoreactivity was found in the postsynaptic density. All receptors were present outside the active zone of nerve terminals. Neurons in the mouse cortex and primary neurons in culture showed immunoreactivity against all five S1PRs, and Ca 2+ imaging revealed that S1P inhibits spontaneous neuronal activity in a dose-dependent fashion. When testing selective agonists for each of the receptors, we found that only S1PR1, S1PR2 and S1PR4 control spontaneous neuronal activity. We conclude that S1PR2 and S1PR4 are located in the active zone of nerve terminals and inhibit neuronal activity. Future studies need to test whether these receptors modulate stimulation-induced neurotransmitter release.
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- Wilhelmsson, Ulrika, 1970, et al.
(författare)
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Nestin Null Mice Show Improved Reversal Place Learning.
- 2020
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Ingår i: Neurochemical research. - : Springer Science and Business Media LLC. - 1573-6903 .- 0364-3190. ; 45:1, s. 215-220
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Tidskriftsartikel (refereegranskat)abstract
- The intermediate filament protein nestin is expressed by neural stem cells, but also by some astrocytes in the neurogenic niche of the hippocampus in the adult rodent brain. We recently reported that nestin-deficient (Nes-/-) mice showed increased adult hippocampal neurogenesis, reduced Notch signaling from Nes-/- astrocytes to the neural stem cells, and impaired long-term memory. Here we assessed learning and memory of Nes-/- mice in a home cage set up using the IntelliCage system, in which the mice learn in which cage corner a nose poke earns access to drinking water. Nes-/- and wildtype mice showed comparable place learning assessed as the incorrect corner visit ratio and the incorrect nose poke ratio. However, during reversal place learning, a more challenging task, Nes-/- mice, compared to wildtype mice, showed improved learning over time demonstrated by the incorrect visit ratio and improved memory extinction over time assessed as nose pokes per visit to the previous drinking corner. In addition, Nes-/- mice showed increased explorative activity as judged by the increased total numbers of corner visits and nose pokes. We conclude that Nes-/- mice exhibit improved reversal place learning and memory extinction, a finding which together with the previous results supports the concept of the dual role of hippocampal neurogenesis in cognitive functions.
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