Neuroprotection and neurogenesis after experimental stroke

Abstract: In this thesis, two potential endogenous mechanisms for neuronal survival and repair have been investigated in a rat model of stroke, middle cerebral artery occlusion (MCAO): signaling of the GDNF family of neurotrophic factors, and neurogenesis from endogenous progenitor cells. As determined by in situ hybridization for GDNF family ligand and receptor genes, MCAO caused widespread upregulation of both components of the functional GDNF receptor, c-Ret and GFRalpha1, indicating that GDNF may be a survival signal in stroke. However, viral vector-mediated GDNF gene transfer to the striatum prior to MCAO could not alleviate long-term neuronal loss or functional deficits, and actually exacerbated neuronal loss in one experiment. Neurogenesis was evaluated by labeling proliferating cells with the thymidine analogue BrdU, and confirming neuronal identity with double-label immunohistochemistry. In the dentate gyrus of the hippocampus, where neurogenesis is continuously ongoing, MCAO caused a pronounced but transient NMDA receptor-mediated increase in neurogenesis. In addition, neurogenesis was also seen in the striatum. Newly formed, immature neurons could be seen migrating from an expanded SVZ into the injured area of the striatum. Many newly formed cells subsequently expressed a marker of mature striatal projection neurons. This thesis demonstrates, that the role of GDNF in stroke is more complex than previously believed, and that high levels of this factor can increase ischemic damage. Furthermore, neurogenesis is stimulated by stroke, and a mechanism for neuronal replacement following ischemic damage exists in the brain. If this response can be stimulated, new strategies for treatment of stroke may be developed.