PT - JOURNAL ARTICLE AU - Satyanarayana Medicherla AU - Andrew A. Protter AU - Jing Ying Ma AU - Ruban Mangadu AU - Ramona Almirez AU - Bruce Koppelman AU - Irene Kerr AU - Tony A. Navas AU - Fabiola Movius AU - Mamatha Reddy AU - Yu-Wang Liu AU - Gregory Luedtke AU - John Perumattam AU - Babu Mavunkel AU - Sundeep Dugar AU - George F. Schreiner TI - Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes AID - 10.1124/jpet.105.097857 DP - 2006 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 99--107 VI - 318 IP - 1 4099 - http://jpet.aspetjournals.org/content/318/1/99.short 4100 - http://jpet.aspetjournals.org/content/318/1/99.full SO - J Pharmacol Exp Ther2006 Jul 01; 318 AB - 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 p38α 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 p38α-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 p38α-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. The American Society for Pharmacology and Experimental Therapeutics