Protective actions of human recombinant basic fibroblast growth factor on MPTP-lesioned nigrostriatal dopamine neurons after intraventricular infusion

Abstract

Basic fibroblast growth factor (bFGF, FGF-2) is a trophic factor for neurons and astrocytes and has recently been demonstrated in the vast majority of dopamine (DA) neurons of the ventral midbrain of the rat. Potential neuroprotective actions of FGF-2 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model have also been reported. The actions of the FGF-2 have now been further analyzed in a combined morphological and behavioural analysis in the MPTP model of the adult black mouse, using a continuous human recombinant FGF-2 (hrFGF-2) intraventricular (i.v.t.) administration in a heparin-containing (10 IU heparin/ml) mock cerebrospinal fluid (CSF) solution. Tyrosine hydroxylase (TH) immunocytochemistry in combination with computer assisted microdensitometry 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 neurons, using stereological methods involving the optical disector (Olympus), 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 behavioral analysis demonstrated an almost full recovery of the MPTP-induced reduction of the locomotor activity after FGF-2 treatment. This action was maintained also 1 week after cessation of treatment. The hrFGF-2 produced an astroglial reaction as determined in the lateral neostriatum and in the substantia nigra (SN) far from the site of the infusion, 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 population in the dorsomedial striatum and the microdensitometric and morphometric evaluation demonstrated an increase in the number, but not in the intensity, of these profiles on the cannulated side, suggesting the possibility that hrFGF-2 stimulates FGF-2 synthesis in astroglial cells with low endogenous FGF-2 IR. These results indicate that hrFGF-2, directly and/or indirectly via astroglia, upon i.v.t. infusion exerts trophic effects on the nigrostriatal DA system and may increase survival of nigrostriatal DA nerve cells exposed to the MPTP neurotoxin

Basic Fibroblast Growth Factor Protects against Rotenone-Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase Pathways

“…In the Parkinsonian brain, there is substantial loss of bFGFimmunoreactive neurons in the SNpc (Tooyama et al, 1993;Tooyama et al, 1994). Both intrastriatal injection and intraventricular infusion of bFGF protect mice in an MPTP model of Parkinson's disease (Otto and Unsicker, 1990;Chadi et al, 1993; Figure 7. bFGF blocks rotenone-induced AIF nuclear translocation in SH-SY5Y cells.…”

Differential astroglial responses in the spinal cord of rats submitted to a sciatic nerve double crush treated with local injection of cultured Schwann cell suspension or lesioned spinal cord extract: implications on cell therapy for nerve repair

“…Animals were deeply anaesthetized with sodium pentobarbital and sacrifi ced by a transcardiac perfusion with 100 ml isotonic saline at room temperature followed by 500 ml of fi xation fl uid (4ºC) over a period of 6 minutes 4,21,22 . The fi xative consisted of 4% paraformaldehyde (w/v, Merck, Germany) in 0.1 M phosphate buffer, pH 6.9.…”

“…Fields of measurements were sampled in the anterior and posterior horns (gray matter), bilaterally. The procedures using a Kontron-Zeiss KS400 image analyzer (Germany) have been described previously 4,21,26,28 . Briefl y, a television camera acquired images from the microscope (63x objective).…”

“…Activated Schwann cells (SC) and satellite cells in the nerve, and also the activation of astrocytes and microglia in the spinal cord and brain regions express the molecules involved in the success or failure of axonal regeneration. Among many other substances, neurotrophic factors possess the ability to modulate regeneration 4,5 . Cooperative responses of central and peripheral glial have been considered to be necessary to the process of regeneration of peripheral fi bers, emphasizing the necessity to study the details of the central glial mechanisms after nerve injury.…”

“…Glial cell proliferation in the dorsal horn induced either by diseases or physical trauma of peripheral nerves has recently become into attention because of the possibility of the glial involvement in naturopathic pain. Both infl ammation 1,[3][4][5][6][7][8][9][10][11][12][13][14][15] and nerve injury 16 are able to activate glial cells in the dorsal horn of the spinal cord, which have been related to development and maintenance of persistent pain states 15,17 .Like the astroglia, which respond in the central nervous system after central or peripheral axotomy, Schwann cells, a type of glia encountered in the peripheral nervous system, which form myelin sheet of nerve axons, are also capable to become reactive after axotomy of peripheral nerves 8,18 . Activated SC are also able to release neurotrophic factors contributing to protect and to stimulate neuronal regeneration 8 .…”