[A mouse model of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced parkinsonism: effect of norepinephrine terminal destruction]

Abstract

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been reported to cause chronic Parkinsonism in humans, primates, and long lasting striatal dopamine depletion in mice. Acute animal models thus produced closely resemble Parkinson's disease. There are, however, two major differences. The one is a lack of Lewy bodies and the other is that norepinephrine system is relatively well preserved in the model. So the acute animal model is better considered a nigrostriatal dopamine deficiency model. We have produced another model by adding N-2-chloroethyl-N-ethyl-2-bromobenzyl-amine (DSP4) to MPTP. This material is known to produce selective destruction of norepinephrine terminal in the central nervous system as well as in the periphery. Both norepinephrine system and dopamine system are severely depressed in this model, and the functional role of norepinephrine system was investigated by comparing two models. 90 male C57 black mice weighing 20-25 grams were used. MPTP (Aldrich) was dissolved in sterile distilled water with 5% ethanol solution. Experimental animals were divided into three groups. i) control group; in this group animals received vehicles alone. ii) MPTP group; in this group, mice received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days, thus total doses of MPTP was 300 mg/kg. iii) MPTP & DSP4 group; in this group animals received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days and at the last day of MPTP injection they received DSP4 50 mg/kg i.p.. 7 to 14 days after the last injection of MPTP both treated and control mice received an intraperitoneal injection of L-DOPA (200 mg/kg & aromatic L-amino acid decarboxylase mg/kg) and the effect of this drug on three groups were investigated by using behavioral, biochemical and histofluorescence method. Histofluorescence studies by GA-FAS method revealed severe reduction of nigrostriatal dopamine in MPTP treated mice. Mesolimbic and mesocortical dopamine systems seemed relatively preserved. There was no apparent changes in locus coeruleus norepinephrine system. In MPTP & DSP4 treated mice marked reduction of norepinephrine terminal fluorescence as well as nigrostriatal dopamine system was observed. Chemical analysis of norepinephrine and dopamine by HPLC confirmed histofluorescence studies. Behavioral studies were analyzed by Automex locomotor activity meter. Marked increase of locomotor activity was observed in MPTP treated mice after L-DOPA administration.(ABSTRACT TRUNCATED AT 400 WORDS)