Flunarizine improves the survival of grafted dopaminergic neurons

Embryonic nigral grafts can survive, reinnervate the striatum and reverse f unctional deficits in both experimental and clinical Parkinsonism. A major drawback is that only around 10% of the implanted dopaminergic neurons surv ive.(4,6,17,22,31) The underlying mechanisms leading to this 90% cell death are not fully understood, but oxidative stress and a substantial loss of n eurotrophic support are likely to be involved. Hypoxia and mechanical traum a, which are unavoidable during tissue preparation, may be a trigger for ce ll death. Recent studies have provided evidence that the type of cell death occurring is, to a large extent, apoptotic.(20,26,31) Flunarizine is an an tagonist of L-, T- and N-type calcium channels,(1,30) which permits calcium entry into cells via a voltage-dependent mechanism. Flunarizine has been s hown to protect neurons against death induced by serum deprivation,(27) ner ve growth factor deprivation,(7,24) oxidative stress,(12,29) axotomy(7,9,24 ) and ischemia.(2,6,13,18) This study was designed to investigate whether f lunarizine can protect grafted embryonic dopaminergic neurons from death wh en implanted in a rat model of Parkinson's disease. Addition of 1 mu M flun arizine inhibited cell death in a suspension of cells derived from the rat' s ventral mesencephalon and when such a treated suspension was injected int o the neostriatum there was a 2.6-fold greater number of surviving dopamine rgic neurons, a doubling of the graft volume and a doubling of the volume o f the host neostriatum innervated by dopaminergic fibers from the graft, co mpared with suspensions not exposed to flunarizine. Furthermore, rats injec ted with cells that had been exposed to flunarizine displayed a greater rec overy of function in the amphetamine-induced rotation test. (C) 1999 IBRO, Published by Elsevier Science Ltd.