Strategies for the augmentation of grafted dopamine neuron survival.

Abstract

The percentage of grafted embryonic DA neurons that survive transplantation is low, estimated at 5-20%. Significant agreement has emerged from the work of research groups worldwide that specific conditions associated with the transplant procedure and post-transplantation interval render grafted mesencephalic cells susceptible to apoptotic death. Detrimental triggers including hypoxia/ischemia, trophic factor withdrawal, and oxidative stress appear to exert the most impact on grafted DA neuron survival. Treatment strategies that aim to reduce or eliminate the triggers of grafted cell death appear to be more successful than approaches that target the intracellular apoptotic cascade. In particular, treatment of mesencephalic cell suspensions with isolated neurotrophic factors (GDNF, BDNF, NT 4/5) as well as glial-derived factors, antioxidant therapies and augmentation of graft vasculature have demonstrated consistent survival promoting effects. Caspase inhibition, although initially quite promising, has not been demonstrated to reliably increase grafted cell survival. Bcl-2 overexpression similarly has yet to prove beneficial, although this may be due to biologically irrelevant levels of bcl-2 present during the critical immediate post-grafting interval. Future strategies will target a "cocktail" approach in which effective treatment agents are combined to maximize grafted DA neuron survival. Refinements in ex vivo transduction parameters will allow for efficient sustained delivery of survival promoting agents to grafted cells. Once identified, the optimal survival-enhancing treatment of grafted primary embryonic DA neurons should also benefit future transplant therapies utilizing alternatively derived DA neurons.