Neuroprotective Effects And Mechanism Of Modafinil On Parkinson's Disease Induced By MPTP

BACKGROUND AND PURPOSE: Parkinson's disease ( PD ) is one of the commonest chronic degeneration of neurons in the older, which disturbs seriously the lives of the aged. The incidence rate of PD is more than 1% in the above 65 years old people. Currently, L-dopa, the most effective drug to alleviate PD symptoms, is often associated with drug treatment localization, the deteriorated curative effect and aggravating side effects. At the same time, neuroprotective treatment is presently an effective way on the parkinsonian symptom and degeneration of neurons in lesion tissue. So it will be an important task to seek for safe and effective neuroprotective compounds. Several recent studies have shown that modafinil, a vigilance-enhancing agent, is also effective in protecting from cerebral ischemia, hypoxia lesions and soman toxic insults and so on. At the same time, it could increase the contents of the inositol and creatine-phosphocreatine pool to improve energy metabolism of brain cells. Moreover, the antagonist of NMDA receptor is accelerated the stimulation of modafinil, which suggests modafinil has the neuroprotective effects on the central nervous system in several pathways. To this day, nobody has reported that its neuroprotective effects and mechanism on the more serious insults of MPTP mouse. In the present study, to more fully explore the neuroprotective effects and mechanism of modafinil on PD, we observed the effects of modafinil on neurochemistry, neurohistopathology and behavior of MPTP-treated mouse.METHODS: The model of Parkinson's disease was induced by intraperitoneally injecting MPTP into C57BL/6J mouse. The effects of modafinil on the behavior of mouse, the distribution of positive cells of tyrosine hydroxylase ( TH ) and Nissle body in the nigrostriate were observed. The contents of dopamine ( DA ) , noradrenaline ( NA ) , 5-hydroxytryptamine ( 5-HT ) , γ-aminobutyric acid ( GABA ) , glutamine ( Glu ) in striatum, and GABA, Glu, malondialdehyde ( MDA ), glutathione(GSH)and ferritin in substantia nigra ( SN ) of model mouse were determined. RESULTS: (1) Modafinil ( 50 and 100 mg/kg ) dose-dependently decreased the defect behaviors induced by MPTP, and prevented the decrease of the contents of striatal DA, the decrease of the number of nigrostriatal TH-positive cells and substantia nigra Nissl body induced by MPTP, which indicated that modafinil has neuroprotection on serious impaired PD mouse induced by MPTP.(2) Modafinil ( 50 and 100 mg/kg ) significantly prevented the increase of the contents of MDA and ferritin in SN, while the decrease of the contents of GSH in SN induced by MPTP. These results suggested that modafinil could scavenge the free radicals and has anti-oxidative effect on PD mouse induced by MPTP.(3) Modafinil ( 50 and 100 mg/kg ) significantly prevented the decrease of the contents of 5-HT and NA in striatum and GABA in SN, while the increase of the contents of GABA in striatum induced by MPTP, but it didn't change the increase of nigrostriatal Glu releases induced by MPTP. Our results suggested that modafinil, by the indirect modulation the striatal NA, 5-HT and nigrostriatal GABAergic activity, prevents the neurotoxicity of MPTP.