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Fibroblast growth factor-2 (FGF-2), locally administered in gelfoam to the striatum of mice treated with the neurotoxic drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has restorative and neuroprotective effects on dopaminergic neurons and associated striatal transmitter systems. Most of the beneficial alterations are apparently indirect. FGF-2 must therefore act through a series of cellular and molecular intermediate steps, which have not been explored. We have previously shown that FGF-2 does not significantly affect the astroglial reaction at the time, when the neuroprotective effect of FGF-2 reaches a peak (Day 11). In this study we have investigated the effect of FGF-2 at earlier time points after MPTP treatment. We report now that as early as 6 h after administration of the gelfoam containing either FGF-2 or control protein, FGF-2 immunoreactivity disappears from astroglial nuclei, while appearing in small ramified GFAP- and S-100-negative cells, most likely microglia. At 18 h, numbers and staining intensities of GFAP-ir astroglial cells are greater in FGF-2- than in cytochrome C-treated animals. At this time FGF-2-ir reappears in astroglia nuclei of cytochrome C-treated animals, but remains undetectable in the striatum carrying the FGF-2-containing gelfoam. Ramified GFAP/S-100-negative presumed microglial cells are now intensely ir for FGF-2. Signs of an FGF-2-mediated astrogliotic reaction are very pronounced at 18 h and 2 days, but no longer at 11 days, when the astrogliosis reaction has become equally strong in FGF-2- and cytochrome C-treated striata. Our results suggest that administration of FGF-2 to the MPTP-lesioned striatum has early effects on astro- and presumed microglia cells, notably on the nuclear FGF-2-ir of astrocytes. These changes may be involved in mediating the neuroprotective effects of FGF-2 in the MPTP-model of Parkinsonism.