Focal ischemic stroke (FIS) is the second leading cause of death in the world and results in a drastic reduction in the quality of life. Despite intense research efforts in the last three decades with more hundreds of drug candidates tested and numerous interventions that have shown promise in pre-clinical studies, all failed in the clinical studies. Astrocytes are the most diverse and numerous glial cells in the central nervous system with intimate contact with neurons. Some of their functions include controlling the development of neural cells and synaptogen, storing and distributing energy substrates and maintaining brain homeostasis. Recent studies have provided evidence that indicate that astrocytes might be a potential target for neural repair in stroke and other brain diseases through their contribution to neuronal regeneration and survival. Glial cell-derived neurotrophic factor (GDNF) is a potent neurotrophic factor that was first isolated from the supernatant of a rat glioma cell-line but now known to also be released from cultured astrocytes. It promotes neuro-progenitor differentiation, synapse formation and neuronal survival. Some studies have shown that GDNF might be useful in stroke therapy due to its neuronal and brain protective abilities. No study has however reported the effect that overexpression or astrocyte specific deletion of GDNF using molecular genetic approaches has on FIS.
In a new study published in Glia, University of Missouri scientists: Nannan Zhang, Zhe Zhang, Rui He, Hailong Li and led by Professor Shinghua Ding looked at the role that endogenous astrocytic GDNF had on brain protection, neuronal survival, oxidative stress and motor function recovery when FIS is induced by photothrombosis. The findings of the research team clearly demonstrated GDNF derived from reactive astrocytes play an important role in improving the long-term outcomes of stroke following FIS.
Following photothrombosis-induced FIS, the authors observed a marked elevation of GDNF in the hemisphere of the ischemic brain, compared to the contralateral hemisphere of ischemic brain and normal brain. The increased expression of GDNF was found more in reactive astrocytes in the peri-infarct region closer to the ischemic core, while the region distant to the ischemic core had less.
No significant effect was found in the synaptic function after the deletion of GDNF in astrocytes under normal conditions. GDNF deletion mediated by GLAST-CreERT2 recombination had no significant effect on the long-term survival of neuronal stem/progenitor. After photothrombosis in GLAST-CreERT2 mice, an increase in the expression of Cre recombinase in reactive astrocytes was noticed. Following the induction of photothrombosis, an increase in neuronal degeneration and hippocampal and brain damage was discovered in GLAST-GDNF−/− KO mice. The reactive astrogliosis that was observed in the peri-infarct region following FIS was found to be attenuated after the deletion of astrocytic GDNF. The deletion of astrocytic GDNF also caused a reduction in the expression of G6PD in reactive astrocytes and an increase in oxidative stress after FIS.
Through carefully designed study, the authors have been able to demonstrate that endogenous GDNF derived from reactive astrocytes, play significant roles in FIS by reducing brain damage and causing neuronal regeneration which promotes brain recovery. Their findings provide evidence that the promotion of anti-oxidant mechanism in reactive astrocytes is a possible treatment strategy for stroke. The authors recommend that further research be carried out to explore how GDNF is released from reactive astrocytes. Positive results from such studies will provide additional evidence that support the target of reactive astrocytes in stroke therapy strategies.
This study was supported by the National Institutes of Health (R01NS069726)
Zhang N, Zhang Z, He R, Li H, Ding S. GLAST-CreERT2 mediated deletion of GDNF increases brain damage and exacerbates long-term stroke outcomes after focal ischemic stroke in mouse model. Glia. 2020;68(11):2395-2414.Go To Glia