Preventive and therapeutic potential of p38 alpha-selective mitogen-activated protein kinase inhibitor in nonobese diabetic mice with type 1 diabetes.
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.
Medicherla
Satyanarayana
S
Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA. smediche@scius.jnj.com
Protter
Andrew A
AA
Ma
Jing Ying
JY
Mangadu
Ruban
R
Almirez
Ramona
R
Koppelman
Bruce
B
Kerr
Irene
I
Navas
Tony A
TA
Movius
Fabiola
F
Reddy
Mamatha
M
Liu
Yu-Wang
YW
Luedtke
Gregory
G
Perumattam
John
J
Mavunkel
Babu
B
Dugar
Sundeep
S
Schreiner
George F
GF
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology* / Q000517:prevention & control*; D005260:Female; D051379:Mice; D016688:Mice, Inbred NOD; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14