PROTECTIVE ACTIONS OF HUMAN RECOMBINANT BASIC FIBROBLAST GROWTH-FACTOR ON MPTP-LESIONED NIGROSTRIATAL DOPAMINE NEURONS AFTER INTRAVENTRICULAR INFUSION

Basic fibroblast growth factor (bFGF, FGF-2) is a trophic factor for n eurons and astrocytes and has recently been demonstrated in the vast m ajority of dopamine (DA) neurons of the ventral midbrain of the rat. P otential neuroprotective actions of FGF-2 in the 1-methyl-4-phenyl-1,2 ,3,6-tetrahydropyridine (MPTP) model have also been reported. The acti ons of the FGF-2 have now been further analyzed in a combined morpholo gical and behavioural analysis in the MPTP model of the adult black mo use, using a continuous human recombinant FGF-2 (hrFGF-2) intraventric ular (i.v.t.) administration in a heparin-containing (10 IU heparin/ml ) mock cerebrospinal fluid (CSF) solution. Tyrosine hydroxylase (TH) i mmunocytochemistry in combination with computer assisted microdensitom etry demonstrated a counteraction of the MPTP-induced disappearance of neostriatal TH-immunoreactive (ir) nerve terminals following the FGF- 2 treatment. Unbiased estimates of the total number of nigral TH ir ne urons, using stereological methods involving the optical disector (Oly mpus), showed that the MPTP-induced reduction in the number of nigral TH ir nerve cell bodies counterstained with cresyl violet (CV; by 56%) was partially counteracted by the FGF-2 treatment (by 26%). The behav ioral analysis demonstrated an almost full recovery of the MPTP-induce d reduction of the locomotor activity after FGF-2 treatment. This acti on was maintained also 1 week after cessation of treatment. The hrFGF- 2 produced an astroglial reaction as determined in the lateral neostri atum and in the substantia nigra (SN) far from the site of the infusio n, indicating that the growth factor may have reached these regions by diffusion to activate the astroglia. Immunocytochemistry revealed FGF -2 immunoreactivity (IR) in the nuclei of the astroglia cell populatio n in the dorsomedial striatum and the microdensitometric and morphomet ric evaluation demonstrated an increase in the number, but not in the intensity, of these profiles on the cannulated side, suggesting the po ssibility that hrFGF-2 stimulates FGF-2 synthesis in astroglial cells with low endogenous FGF-2 IR. These results indicate that hrFGF-2, dir ectly and/or indirectly via astroglia, upon i.v.t. infusion exerts tro phic effects on the nigrostriatal DA system and may increase survival of nigrostriatal DA nerve cells exposed to the MPTP neurotoxin.