Investigating th effects of lenti-virus mediated GDNF expression on functional recovery, brain plasticity and neurogenesis after transient focal cerebral ischemia in mice

Stroke affects lives of many people adversely, although they survive after an attack. Administration of anticoagulants, tissue plasminogen activators (tPA) and statins are current medications for ischemic stroke, clinically. These treatments mediate to prevent further damage, but not sufficient for restoration of functional deficiencies. Numerous different therapeutic factors providing partial recovery have been identified, including neuroprotective molecules, neuromodulators, neurotrophic agents, growth factors, hormones, cell-based systems, etc. Glial cell-line derived neurotrophic factor (GDNF) is one of the powerful candidate therapeutics for stroke treatment. Direct administration of recombinant GDNF protein or upregulation of its expression via genetic manipulation was applied to animal models of brain ischemia by many researchers. In this thesis, prolonged expression of GDNF was achieved by lenti-viral vectors which was administered intracerebrally. Due to its capability to provide sustained expression by integrating host genome and transduce non-dividing cells, lenti-viral vectors were used. This was the first time usage of lenti-viral mediated GDNF gene transfer as a therapeutic purpose for stroke. Measurements of infarct size, swelling and neuronal survival showed an acute improvement triggered by means of GDNF's neuroprotective effects. Also, neuroplasticity was analysed at functional level by behavioral tests and at a molecular level by axonal projection analysis which showed an apparent recovery at post-ischemic day 55. Additionally, DNA fragmentation analysis, neurogenesis analysis, glial scar analysis and protein expression analysis of growth inhibiting factors were performed and showed improvements in neuronal recovery.