Preventive and Therapeutic Potential of P38 Alpha-selective Mitogen-activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes.
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The Journal of pharmacology and experimental therapeutics
- Publish Date: Jul 2006
- ISSN: 0022-3565
- Volume: 318
- Issue: 1
- Pages: 99-107
- Medium: Print
- Language: English
- Citation (JAMA): Medicherla Satyanarayana, Protter Andrew A, Ma Jing Ying, et al. Preventive and Therapeutic Potential of P38 Alpha-selective Mitogen-activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes.. J. Pharmacol. Exp. Ther. Jul 2006;318:99-107
Abstract
Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38alpha MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse. In preventive treatment studies, SD-169 significantly reduced p38 and HSP60 expression in T cells of the pancreatic beta islets. Following treatment, the incidence of diabetes as determined by blood glucose levels was significantly lower, and immuno-histochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5+ T cell infiltration in the SD-169 treatment group as compared with untreated NOD mice. In therapeutic studies using mildly and moderately hyperglycemic NOD mice, SD-169 treatment lowered blood glucose and improved glucose homeostasis. Furthermore, following cessation of SD-169 treatment, NOD mice showed significant arrest of diabetes. In conclusion, we report that this p38alpha-selective inhibitor prevents the development and progression of diabetes in NOD mice by inhibiting T cell infiltration and activation, thereby preserving beta cell mass via inhibition of the p38 MAPK signaling pathway. These results have bearing on current prophylactic and therapeutic protocols using p38alpha-selective inhibitors in the prediabetic period for children at high risk of type 1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.
Mesh Headings (Keywords): Animals, Diabetes Mellitus, Type 1, Female, Mice, Mice, Inbred NOD, Mitogen-Activated Protein Kinase 14, Protein Kinase Inhibitors
Check for Full Text / PubMed Unique Identifier (PMID): 16603672
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