Survival of Cultured and Grafted Embryonic Dopaminergic Neurones - Effects of hypothermia and prevention of oxidative stress

Abstract: Transplantation of embryonic dopaminergic neurones can ameliorate symptoms in Parkinson’s disease, but a major obstacle for clinical transplantations to overcome is the low survival (typically 5-10%) of implanted nigral neurones. If cell death in nigral grafts can be prevented, less embryonic tissue would be needed per transplantation session and hence more patients could receive intracerebral grafts as a therapy for Parkinson’s disease. Cell death in embryonic dopaminergic implants is induced by trauma during donor tissue preparation, and continues after graft implantation into the adult brain. The neuroprotective effect of different lazaroids (synthetic inhibitors of lipid peroxidation) was demonstrated in different in vitro systems, e.g. cell death induced by serum deprivation in cultures and free radical-induced neuronal death in cell suspensions. Moreover, we showed that resveratrol, which is found e.g. in red wine, can act as an antioxidant and prevent free radical-induced death in mesencephalic cells. However, we also found that in vitro models may not always be reliable when screening neuroprotective agents for transplantation. Results presented in this thesis also show that systemic treatment of graft recipients with the lazaroid Tirilazad Mesylate during the first 3 days after transplantation improves survival of implanted dopaminergic neurones, indicating that oxidative stress in the host brain contributes to death of the grafted neurones. In contrast, spin-trap agents did not affect graft survival in a similar paradigm. Interestingly, mild hypothermia (32-33°C) of the graft recipient during transplantation and for the following 90 min improve the survival and function of nigral grafts, yielding a survival rate of approximately 50% of the transplanted dopaminergic neurones. Findings from transplantation studies described above suggest that a substantial amount of cell death in nigral grafts occur during the immediate period after implantation. Therefore, strategies to optimise graft survival should be applied during different stages of the transplantation procedure, both before and after implantation of embryonic dopaminergic neurones.