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Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells' degeneration induced by inflammatory processes after lipopolysaccharide injection.
Neuroscience. 2006 Jul 21; 140(4):1157-68.N

Abstract

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.

Authors+Show Affiliations

Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16713109

Citation

Ruano, D, et al. "Role of P38 and Inducible Nitric Oxide Synthase in the in Vivo Dopaminergic Cells' Degeneration Induced By Inflammatory Processes After Lipopolysaccharide Injection." Neuroscience, vol. 140, no. 4, 2006, pp. 1157-68.
Ruano D, Revilla E, Gavilán MP, et al. Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells' degeneration induced by inflammatory processes after lipopolysaccharide injection. Neuroscience. 2006;140(4):1157-68.
Ruano, D., Revilla, E., Gavilán, M. P., Vizuete, M. L., Pintado, C., Vitorica, J., & Castaño, A. (2006). Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells' degeneration induced by inflammatory processes after lipopolysaccharide injection. Neuroscience, 140(4), 1157-68.
Ruano D, et al. Role of P38 and Inducible Nitric Oxide Synthase in the in Vivo Dopaminergic Cells' Degeneration Induced By Inflammatory Processes After Lipopolysaccharide Injection. Neuroscience. 2006 Jul 21;140(4):1157-68. PubMed PMID: 16713109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells' degeneration induced by inflammatory processes after lipopolysaccharide injection. AU - Ruano,D, AU - Revilla,E, AU - Gavilán,M Paz, AU - Vizuete,M L, AU - Pintado,C, AU - Vitorica,J, AU - Castaño,A, Y1 - 2006/05/18/ PY - 2005/10/13/received PY - 2006/02/24/revised PY - 2006/02/25/accepted PY - 2006/5/23/pubmed PY - 2006/10/27/medline PY - 2006/5/23/entrez SP - 1157 EP - 68 JF - Neuroscience JO - Neuroscience VL - 140 IS - 4 N2 - 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. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/16713109/Role_of_p38_and_inducible_nitric_oxide_synthase_in_the_in_vivo_dopaminergic_cells'_degeneration_induced_by_inflammatory_processes_after_lipopolysaccharide_injection_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(06)00325-3 DB - PRIME DP - Unbound Medicine ER -