title: 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.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Danny Thomas Research Tower, Room D2025E, Mail Stop 323, Memphis, TN 38105-2794, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pattarini
authors.forename: R J
authors.initials: RJ
authors.lastname: Smeyne
authors.forename: J I
authors.initials: JI
authors.lastname: Morgan
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002470:Cell Survival / Q000235:genetics; D018925:Chemokines / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004660:Encephalitis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism*; D013045:Species Specificity; D013997:Time Factors
chemical_list: D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine