Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice

Abstract

The specific mechanisms underlying the restorative effects of adrenal chromaffin grafts in experimental parkinsonism are still obscure. Recent findings indicated an involvement of graft-induced trophic interactions in the course of recovery-related events. Evidence that basic fibroblast growth factor (bFGF), a potent trophic protein for neurons, (1) is present in chromaffin cells (Blottner et al., 1989) and (2) exerts trophic activities on embryonic mesencephalic neurons in vitro (Ferrari et al., 1989) provided the rationale for administering bFGF in gel foam implants unilaterally to the striatum of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned mice. Simultaneous bFGF/MPTP treatment diminished bilaterally the reduction of striatal dopamine (DA) levels observed in cytochrome c/MPTP-treated mice and led to an ipsilateral reappearance of tyrosine hydroxylase (TH)-like immunoreactive fibers, most notably adjacent to the implant, 2 weeks after the surgery. Determinations of TH activities and TH immunoblotting demonstrated that bFGF almost fully reversed the loss of TH activity on either side but restored TH protein more on the ipsilateral than on the contralateral side. Furthermore, differences in dihydroxyphenylacetic acid levels, which were about twice as high on the contralateral side yet still reduced with respect to untreated mice, supported our assumption that the molar TH activity was increased on the untreated side, possibly due to an intrinsic compensatory up- regulation. Delayed administration of bFGF starting 8 d after the MPTP treatment was equally effective with regard to morphological parameters. Our results suggest that bFGF partially prevents the deleterious chemical and morphological consequences of an MPTP-mediated nigrostriatal lesion. Thus, bFGF mimics at least the morphological effects of chromaffin cell grafts to the MPTP-lesioned brain.