Inhibitors of p38 MAP kinase increase the survival of transplanted dopamine neurons

Fetal cell transplantation therapies are being developed for the treatment of a number of neurodegenerative disorders including Parkinson's disease [1 0-12,21,22,24,36,43], Massive apoptotic cell death is a major limiting fact or for the success of neurotransplantation. We have explored a novel protei n kinase pathway for its role in apoptosis of dopamine neurons. We have dis covered that inhibitors of p38 MAP kinase (the pyridinyl imidazole compound s: PD169316, SB203580, and SB202190) improve survival of rat dopamine neuro ns in vitro and after transplantation into hemiparkinsonian rats. In embryo nic rat ventral mesencephalic cultures, serum withdrawal led to 80% loss of dopamine neurons due to increased apoptosis. Incubation of the cultures wi th p38 MAP kinase inhibitors at the time of serum withdrawal prevented dopa minergic cell death by inhibiting apoptosis. In the hemiparkinsonian rat, p reincubation of ventral mesencephalic tissue with PD169316 prior to transpl antation accelerated behavioral recovery and doubled the survival of transp lanted dopamine neurons. We conclude that inhibitors of stress-activated pr otein kinases improve the outcome of cell transplantation by preventing apo ptosis of neurons after grafting. (C) 2001 Elsevier Science B.V. All rights reserved.