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Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). With the exception of a few rare familial forms of the disease, the precise molecular mechanisms underlying PD are unknown. Inflammation is a common finding in the PD brain, but due to the limitation of postmortem analysis its relationship to disease progression cannot be established. However, studies using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have also identified inflammatory responses in the nigrostriatal pathway that precede neuronal degeneration in the SNpc. To assess the pathological relevance of these inflammatory responses and to identify candidate genes that might contribute to neuronal vulnerability, we used quantitative reverse-transcription polymerase chain reaction (qRT-PCR) to measure mRNA levels of 11 cytokine and chemokine encoding genes in the striatum of MPTP-sensitive (C57BL/6J) and MPTP-insensitive (Swiss Webster, SWR) mice following administration of MPTP. The mRNA levels of all 11 genes changed following MPTP treatment, indicating the presence of inflammatory responses in both strains. Furthermore, of the 11 genes examined only 3, interleukin 6 (Il-6), macrophage inflammatory protein 1 alpha/CC chemokine ligand 3 (Mip-1alpha/Ccl3) and macrophage inflammatory protein 1 beta/CC chemokine ligand 4 (Mip-1beta/Ccl4), were differentially regulated between C57BL/6J and SWR mice. In both mouse strains, the level of monocyte chemoattractant protein 1/CC chemokine ligand 2 (Mcp-1/Ccl2) mRNA was the first to increase following MPTP administration, and might represent a key initiating component of the inflammatory response. Using Mcp-1/Ccl2 knockout mice backcrossed onto a C57BL/6J background we found that MPTP-stimulated Mip-1alpha/Ccl3 and Mip-1beta/Ccl4 mRNA expression was significantly lower in the knockout mice; suggesting that Mcp-1/Ccl2 contributes to MPTP-enhanced expression of Mip-1alpha/Ccl3 and Mip-1beta/Ccl4. However, stereological analysis of SNpc neuronal loss in Mcp-1/Ccl2 knockout and wild-type mice showed no differences. These findings suggest that it is the ability of dopaminergic SNpc neurons to survive an inflammatory insult, rather than genetically determined differences in the inflammatory response itself, that underlie the molecular basis of MPTP resistance.

SUBMITTER: Pattarini R

PROVIDER: S-EPMC1894756 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson's disease.

Pattarini R R Smeyne R J RJ Morgan J I JI

Neuroscience 20070129 2

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). With the exception of a few rare familial forms of the disease, the precise molecular mechanisms underlying PD are unknown. Inflammation is a common finding in the PD brain, but due to the limitation of postmortem analysis its relationship to disease progression cannot be established. However, studies using the 1-methyl-4-phenyl-1,2,3,6-tetrahyd ...[more]

PMID: 17258864

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Project description:The etiology of idiopathic Parkinson's disease is thought to involve interplay between environmental factors and predisposing genetic traits, although the identification of genetic risk factors remain elusive. The neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) produces parkinsonian-like symptoms and pathology in mice and humans. As sensitivity to MPTP is genetically determined in mice this provides an opportunity to identify genes and biological mechanisms that modify the response to an exogenous agent that produces a Parkinson's disease-like condition. MPTP primarily targets dopaminergic nerve terminals in the striatum and elicits changes in striatal gene expression. Therefore, we used Affymetrix and qRT-PCR technology to characterize temporal mRNA changes in striatum in response to MPTP in genetically MPTP-sensitive, C57BL/6J, and MPTP-resistant Swiss Webster and BCL2-associated X protein (Bax)-/- mice. We identified three phases of mRNA expression changes composed of largely distinct gene sets. An early response (5 h) occurred in all strains of mice and multiple brain regions. In contrast, intermediate (24 h) and late (72 h) phases were striatum specific and much reduced in Swiss Webster, indicating these genes contribute and/or are responsive to MPTP-induced pathology. However, Bax-/- mice have robust intermediate responses. We propose a model in which the acute entry of MPP+ into dopaminergic nerve terminals damages them but is insufficient per se to kill the neurons. Rather, we suggest that the compromised nerve terminals elicit longer lasting transcriptional responses in surrounding cells involving production of molecules that feedback on the terminals to cause additional damage that results in cell death. In Swiss Webster, resistance lies upstream in the cascade of events triggered by MPTP and uncouples the acute events elicited by MPTP from the damaging secondary responses. In contrast, in Bax-/- mice resistance lies downstream in the cascade and suggests enhanced tolerance to the secondary insult rather than its attenuation.

Dataset Information

Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson's disease.

Publications

Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson's disease.

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