Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to elucidate the inflammatory and apoptotic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a model of Parkinson's disease. Our results showed that mutant mice lacking the caspase-11 gene were significantly more resistant to the effects of acute treatment with MPTP than their wild-type mice. Thus, the neurotoxicity of MPTP seems to be mediated by the induction of both mitochondrial dysfunction and free radical generation. Previously, we showed that overexpression of the Apaf-1 dominant-negative inhibitor inhibited the mitochondrial apoptotic cascade in chronic MPTP treatment but not in acute MPTP treatment. The present results indicate that MPTP neurotoxicity may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade.
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PMID:Caspase-11 mediates inflammatory dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. 1498 26

Accumulating evidences suggest that neuroinflammation is involved in the progressive death of dopaminergic neurons in Parkinson's disease. Several studies have shown that intranigral injection of lipopolysaccharide induces inflammation in the substantia nigra leading to death of tyrosine hydroxylase-positive cells. To better understand how the inflammatory response gives rise to neurotoxicity we induced inflammation in substantia nigra by injecting lipopolysaccharide. The damage of substantia nigra dopaminergic neurons was evaluated by immunohistochemistry, reverse transcription-PCR and Western blot analysis of tyrosine hydroxylase. In parallel, activation of microglial cells, a hallmark of inflammation in CNS, was revealed by immunohistochemistry. Similarly the expression of molecules involved in the inflammatory response and apoptotic pathway was also tested, such as cytokines (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), inducible nitric oxide synthase and caspase-11. Tyrosine hydroxylase expression (both mRNA and protein) started to decrease around 3 days post-injection. At the mRNA level, our results showed that the cytokines expression peaked shortly (3-6 h) after lipopolysaccharide injection, followed by the induction of inducible nitric oxide synthase and caspase-11 (14 h). However, inducible nitric oxide synthase protein peaked at 24 h and lasted for 14 days. The lipopolysaccharide-induced loss of substantia nigra dopaminergic neurons was partially inhibited by co-injection of lipopolysaccharide with S-methylisothiourea, an inducible nitric oxide synthase inhibitor. Co-injections of lipopolysaccharide with SB203580, a p38 MAP kinase inhibitor, reduced inducible nitric oxide synthase and caspase-11 mRNA expression, and also rescued dopaminergic neurons in substantia nigra. In summary, this is the first report to describe in vivo the temporal profile of the expression of these inflammatory mediators and proteins involved in dopaminergic neuronal death after intranigral injection of lipopolysaccharide. Moreover data strongly support that lipopolysaccharide-induced dopaminergic cellular death in substantia nigra could be mediated, at least in part, by the p38 signal pathway leading to activation of inducible nitric oxide synthase and caspase-11.
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PMID:Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells' degeneration induced by inflammatory processes after lipopolysaccharide injection. 1671 9

Enhancement of neurogenesis could be a suitable treatment approach to up-regulate dopaminergic neurons in Parkinson's disease (PD). In the present study, we focused on the kinetics of the subventricular zone (SVZ) in a mouse model of PD induced by MPTP injection. We showed recently the proliferation potential of neuronal stem cells (NSCs) prepared from the olfactory bulb of an animal model of PD [Hayakawa, H., Hayashita-Kinoh, H., Nihira, T., Seki, T., Mizuno, Y., Mochizuki, H., 2007. The isolation of neural stem cells from the OB of Parkinson's disease model. Neurosci. Res.]. In this study, we examined the relationship between proliferation and differentiation of NSCs in SVZ of both acute and chronic PD models. Only acute MPTP treatment significantly increased the areas of glial fibrillary acidic protein (GFAP)-expressing cells and decreased the areas of polysialylated neural cell adhesion molecule (PSA-NCAM)-expressing cells in the SVZ. In the case of caspase-11 knockout mice, MPTP did not induce alteration in the areas of GFAP-expressing cells and PSA-NCAM-expressing cells. Our results suggest that neuroinflammation related to the caspase-11 cascade in the striatum regulates differentiation of neural stem cells in the SVZ of our mouse model of PD.
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PMID:Alteration in the differentiation-related molecular expression in the subventricular zone in a mouse model of Parkinson's disease. 1796 13