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.

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Recently, the induction of neuroinflammation received much attention as a key pathway involved in MPTP-induced pathogenesis and progression ( [10,164,181]). Langston et al found that in postmortem examination of brains from humans exposed to MPTP activated microglia were present up to 16 years after exposure, indicating a protracted inflammatory response [134].…”

Effects of 1,2,3,4-Tetrahydroisoquinoline Derivatives on Dopaminergic Spontaneous Discharge in Substantia Nigra Neurons in Rats

“…Although 1-MeTIQ prevents the MPP + -induced inhibition of complex I of the mitochondrial respiratory chain [48], the present result showed that 1-MeTIQ antagonized the effect of MPTP outside the nigral dopaminergic neurons. In addition, MPTP induces gliosis and microglial activation, which likely contribute to the injury to dopaminergic neurons [49,50]. 1-MeTIQ may have affected the cells surrounding dopaminergic neurons.…”

Ethyl-eicosapentaenoate modulates changes in neurochemistry and brain lipids induced by parkinsonian neurotoxin 1-methyl-4-phenylpyridinium in mouse brain slices

“…Similar to our findings, Ambrosio et al (1996) found a bottom effect of MPP + concentration on dopamine levels, with the largest decline of striatal dopamine level between 0 and 25 μM (2 h incubation) and no substantial further decline beyond this concentration. Since gene expression may be more expressed at 4 h MPP + treatments rather than 2 h (Pattarini et al, 2007), a 4 hour incubation time was presently chosen.…”