Fibroblast growth factor 9 prevents MPP⁺‐induced death of dopaminergic neurons and is involved in melatonin neuroprotection in vivo and in vitro

Abstract

Abbreviations used: BDNF, brain-derived neurotrophic growth factor; BSA, bovine serum albumin; DA, dopamine; FGF, fibroblast growth factor; GDNF, glial cell line-derived neurotrophic factor; MAP2, microtubule associated protein 2; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; PD, Parkinson's disease; TH, tyrosine hydroxylase; TH-ir, TH-immunoreactive. AbstractOxidative stress and down-regulated trophic factors are involved in the pathogenesis of nigrostriatal dopamine(DA)rgic neurodegeneration in Parkinson's disease. Fibroblast growth factor 9 (FGF9) is a survival factor for various cell types; however, the effect of FGF9 on DA neurons has not been studied. The antioxidant melatonin protects DA neurons against neurotoxicity. We used MPP + to induce neuron death in vivo and in vitro and investigated the involvement of FGF9 in MPP + intoxication and melatonin protection. We found that MPP + in a dose-and time-dependent manner inhibited FGF9 mRNA and protein expression, and caused death in primary cortical neurons. Treating neurons in the substantia nigra and mesencephalic cell cultures with FGF9 protein inhibited the MPP + -induced cell death of DA neurons. Melatonin co-treatment attenuated MPP + -induced FGF9 down-regulation and DA neuronal apoptosis in vivo and in vitro. Co-treating DA neurons with melatonin and FGF9-neutralizing antibody prevented the protective effect of melatonin. In the absence of MPP + , the treatment of FGF9-neutralizing antibody-induced DA neuronal apoptosis whereas FGF9 protein reduced it indicating that endogenous FGF9 is a survival factor for DA neurons. We conclude that MPP + down-regulates FGF9 expression to cause DA neuron death and that the prevention of FGF9 down-regulation is involved in melatonin-provided neuroprotection.

Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP+ toxicity

“…Because MPP + is the major active and toxic metabolite of MPTP and uptake by dopamine transporter, but cannot cross the blood-brain barrier (Dauer and Przedborski, 2003), we directly infused MPP + into the rat striatum to avoid the effect of exercise on MPTP metabolism and to specifically destroy the nigral dopamine neurons (Chen et al, 2002;Huang et al, 2009;Hung et al, 2008). One microliter of 50 mM MPP + (Sigma-Aldrich, St. Louis, MO, USA) or PBS was infused into the right striatum through a 30-gauge stainless steel cannula connected to a 10 μl microsyringe (Hamilton Co., Reno, NV) in an infusion rate of 0.1 μl/min using a syringe pump and kept still for 5 min before being slowly withdrawn to minimize possible physical damage to the brain tissue.…”

“…Our previous studies have shown that the antioxidant action of melatonin attenuates the elevation of ROS and the reduction of glutathione thus preventing dopaminergic neuron death due to 1-methyl-4-phenylpyridine (MPP + , the major bioactive and toxic metabolite of MPTP) toxicity in vivo and in vitro (Chen et al, 2002;Chuang and Chen, 2004;Huang et al, 2009). A significantly lower level of glutathione was also found in brains of patients with PD (Elokda et al, 2010;Sian et al, 1994), while dopaminergic glutathione depletion resulted in age-related nigrostriatal dopaminergic neurodegeneration (Chinta et al, 2007).…”

Fibroblast Growth Factor 9 Suppresses Striatal Cell Death Dominantly Through ERK Signaling in Huntington’s Disease

“…In neurodegenerative diseases, FGF9 signaling has been reported to affect cellular or pathological features in Alzheimer's disease (AD) and Parkinson's disease (PD) [5,[15][16][17]. For example, FGF9 is surrounding senile plaques in AD brain [15,18].…”

“…For example, FGF9 is surrounding senile plaques in AD brain [15,18]. In PD models, FGF9 provide neuronprotective effects from apoptosis through γ-glutamylcysteine synthetase and heme oxygenase 1 expression [5,16]. These suggest the involvement of FGF9 signaling in neuropathology and disease progression of AD and PD.…”

Fibroblast growth factor 9 is a novel modulator of negative affect

“…Functionally, the literature suggests that FGF9 may promote cell survival. For example, FGF9 acts as a survival factor for nigrostriatal and mesencephalic dopamine neurons (24), and FGF9 treatment can increase the survival and soma size of cultured basal forebrain cholinergic neurons (25). FGF9 also weakly promoted proliferation and survival of cultured adult subventricular neural progenitor cells, inhibiting astrocyte differentiation (26).…”