Spinal cord degeneration in C57BL/6N mice following induction of experimental parkinsonism with MPTP

Abstract

We examined neurodegeneration in spinal cord (SC) and role of such extra‐nigral degeneration in MPTP‐induced experimental parkinsonism in C57BL/6N mice. HPLC‐photodiode array analysis confirmed presence of the active neurotoxin MPP+ in SC after single injection of MPTP (25 mg/kg, i.p.). Mitochondrial enzyme monoamine oxidase‐B (MAO‐B) responsible for in vivo conversion of MPTP to MPP+ was inhibited in SC by pre‐treatment with l‐deprenyl, a specific inhibitor of MAO‐B. Besides in vitro conversion of MPTP to MPP+ occurred by SC mitochondrial preparation, which was inhibited by l‐deprenyl implicating SC as a specific target of MPTP‐neurotoxicity. Double immunofluorescent labeling and spectrofluorimetric assay via kynuramine oxidation showed MAO‐B expression and activity in SC neurons. Localization of dopamine transporter immunoreactivity in SC along with specific uptake of 3H‐MPP+ by SC synaptosomal preparation further confirmed SC as target of MPTP‐neurotoxicity. Compared with control, increased neuronal death on the seventh day in SC of mice injected with MPTP (2 × 25 mg/kg, at 6 h interval) strongly suggested SC degeneration in pre‐symptomatic phase of MPTP‐induced experimental parkinsonism. Such extra‐nigral neurodegeneration in Parkinson’s disease indicated novel molecular mechanism preceding nigrostriatal degeneration and suggested designing broad therapeutic intervention for this complex movement disorder.

Changes of gene expression profiles in the cervical spinal cord by acupuncture in an MPTP-intoxicated mouse model: Microarray analysis

“…The report showed that the presence of the 1-methyl-4-phenylpyridinium ion (MPP + ) form in the synaptosomal fraction of the spinal cords following MPTP intoxication, along with monoamine oxidase-B (MAO-B) activity and DAT immunolocalization in the spinal cord neurons, resulted from the transformation of MPTP to MPP + in the spinal cords. This transformation is well recognized as the initial reaction in the induction of nigrostriatal degeneration by MPTP intoxication, and finally may result in spinal cord neuro-intoxication through MPTP intoxication in the report (Samantaray et al, 2008). In actuality, neuronal death was observed in the spinal cords of pre-symptomatic mice following the intraperitoneal MPTP intoxication, which suggested extra-nigral degeneration by MPTP, at least in part, in the spinal cord (Samantaray et al, 2008).…”

“…These observations imply that Ube2l6 plays a role in the ISGylation of proteins which is part of many cellular pathways, but may not be involved in the conventional proteasome-mediated protein degradation. It was shown that MPTP intoxication induces the degeneration of dorsal and ventral horns in the spinal cords of mice (Samantaray et al, 2008). The report showed that the presence of the 1-methyl-4-phenylpyridinium ion (MPP + ) form in the synaptosomal fraction of the spinal cords following MPTP intoxication, along with monoamine oxidase-B (MAO-B) activity and DAT immunolocalization in the spinal cord neurons, resulted from the transformation of MPTP to MPP + in the spinal cords.…”

“…The results of this study suggest that acupuncture at the acupoints may affect the expression of the target genes in the cervical spinal cord which can be damaged by MPTP intoxication (Samantaray et al, 2008).…”

“…Animal models of parkinsonism are known to be produced by loading neurotoxic compounds such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), pesticides and other parkinsonism agents (Emborg, 2004;Emborg, 2007). It was especially reported that MPTP induces the degeneration of spinal cord in a mouse model of MPTP intoxication (Samantaray et al, 2008). Pharmaceutical studies have been conducted using these animal models of PD-like neuropathological features as well as using actual PD patients (Dutta et al, 2008;Etminan et al, 2003;Hamaue 2000;Kasture et al, 2009;Liang et al, 2007;Neef and van Laar, 1999;Yano et al, 2009).…”

“…As the genes which may be related to the inhibition of nigrostriatal neurodegeneration by acupuncture at the acupoint GB34 in the MPTP model need to be further elucidated (Hong et al, 2010) and the spinal cord can be damaged by MPTP intoxication (Samantaray et al, 2008), this study investigated the gene expression profile changes in the cervical spinal cord using the whole transcript GeneChip microarray after acupuncture at the acupoints GB34 and LR3 in the MPTP-induced parkinsonism model. The results of this study suggest that acupuncture at the acupoints may affect the expression of the target genes in the cervical spinal cord which can be damaged by MPTP intoxication (Samantaray et al, 2008).…”