| First Author | Zhang N | Year | 2020 |
| Journal | Glia | Volume | 68 |
| Issue | 11 | Pages | 2395-2414 |
| PubMed ID | 32497340 | Mgi Jnum | J:297573 |
| Mgi Id | MGI:6474054 | Doi | 10.1002/glia.23848 |
| Citation | Zhang N, et al. (2020) GLAST-CreER(T2) mediated deletion of GDNF increases brain damage and exacerbates long-term stroke outcomes after focal ischemic stroke in mouse model. Glia 68(11):2395-2414 |
| abstractText | 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. |
