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GLAST-CreER^T2 mediated deletion of GDNF increases brain damage and exacerbates long-term stroke outcomes after focal ischemic stroke in mouse model.

ABSTRACT: Focal ischemic stroke (FIS) is a leading cause of human death. Glial scar formation largely caused by reactive astrogliosis in peri-infarct region (PIR) is the hallmark of FIS. Glial cell-derived neurotrophic factor (GDNF) was originally isolated from a rat glioma cell-line supernatant and is a potent survival neurotrophic factor. Here, using CreER^T2 -LoxP recombination technology, we generated inducible and astrocyte-specific GDNF conditional knockout (cKO), that is, GLAST-GDNF^-/- cKO mice to investigate the effect of reactive astrocytes (RAs)-derived GDNF on neuronal death, brain damage, oxidative stress and motor function recovery after photothrombosis (PT)-induced FIS. Under non-ischemic conditions, we found that adult GLAST-GDNF^-/- cKO mice exhibited significant lower numbers of Brdu+, Ki67+ cells, and DCX+ cells in the dentate gyrus (DG) in hippocampus than GDNF floxed (GDNF^f/f ) control (Ctrl) mice, indicating endogenous astrocytic GDNF can promote adult neurogenesis. Under ischemic conditions, GLAST-GDNF^-/- cKO mice had a significant increase in infarct volume, hippocampal damage and FJB+ degenerating neurons after PT as compared with the Ctrl mice. GLAST-GDNF^-/- cKO mice also had lower densities of Brdu+ and Ki67+ cells in the PIR and exhibited larger behavioral deficits than the Ctrl mice. Mechanistically, GDNF deficiency in astrocytes increased oxidative stress through the downregulation of glucose-6-phosphate dehydrogenase (G6PD) in RAs. In summary, our study indicates that RAs-derived endogenous GDNF plays important roles in reducing brain damage and promoting brain recovery after FIS through neural regeneration and suggests that promoting anti-oxidant mechanism in RAs is a potential strategy in stroke therapy.

SUBMITTER: Zhang N

PROVIDER: S-EPMC8261898 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background. Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets. Results. Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 hours post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female (n = 12) MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCAs as compared with the control MCAs from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05; n = 23). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common). Conclusions. The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCAs, and to a less pronounced degree in the non-occluded MCAs. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<1% of differentially expressed genes) validated for this microarray did not reveal any sex differences.

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GLAST-CreERT2 mediated deletion of GDNF increases brain damage and exacerbates long-term stroke outcomes after focal ischemic stroke in mouse model.

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GLAST-CreER^T2 mediated deletion of GDNF increases brain damage and exacerbates long-term stroke outcomes after focal ischemic stroke in mouse model.