Antinociceptive action of a p38α MAPK inhibitor, SD-282, in a diabetic neuropathy model

Abstract

Diabetes can induce a bewildering list of sensory changes, including alteration in pain sensitivity. Painful diabetic neuropathy is refractory to most common analgesics. This study examined the effect of a p38alpha MAPK inhibitor, SD-282, on mechanical allodynia, thermal hyperalgesia, and formalin-evoked nociception in streptozotocin-induced diabetic rats. Four-week diabetic rats exhibited mechanical allodynia, decreased mechanical thresholds, and C- and Adelta-fiber mediated thermal hyperalgesia. Mechanical and thermal responses were measured in diabetic rats following acute and repeated intraperitoneal administration of vehicle, 15 or 45 mg/kg SD-282. Mechanical allodynia was reversed by acute and repeated administration of 15 and 45 mg/kg SD-282. Repeated administration of 15 or 45 mg/kg SD-282 prevented the exacerbation of C-, but not Adelta-fiber, mediated thermal hyperalgesia. Repeated administration of 45 mg/kg SD-282 attenuated flinching behaviors during the quiescent period and the second phase of the formalin response in diabetic rats. Acute and repeated administration of 15 or 45 mg/kg SD-282 had no effect on mechanical, thermal or formalin responses in age-matched control rats. These results indicate a potential therapeutic value of p38alpha MAPK inhibitors in the treatment of aberrant pain sensitivity produced by diabetes.

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

“…Our data are supported by a recent study that reported that a p38 MAPK inhibitor in combination with dexamethasone caused a greater suppression of gene expression induced by LPS in monocyte-derived macrophages or AMs [10]. The p38 MAPK inhibitor, SD282, is an indole-5-carboxamide selective p38a MAPK inhibitor demonstrating a 14.3-fold greater potency for p38a compared with p38b [8,9]. No detectable effect on other closely related kinases such as p38d, p38c, jun-N-terminal kinase and p38 activating kinases at concentrations up to 50 mM in human PBMCs has been observed [8] and, therefore, these effects are likely to result from the selective inhibition of the p38a MAPK isoform.…”

“…?well -1 ) were purified by adhesion to plastic wells for 4 h and then exposed for 18 h to lipopolysaccharide (LPS; 10 mg?mL -1 ) in the presence or absence of dexamethasone (10 -6 M) or of a selective p38 MAPK inhibitor, SD282 (10 -7 M; Scios Inc, Freemont, CA, USA) [8,9] or both. p38 MAPK phosphorylation To determine p38 MAPK activity, PBMCs were stimulated with LPS overnight in the presence or absence of dexamethasone (10 -8 M) and/or GW-A (10 -9 M).…”

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

“…The IC 50 values of SD-282 for p38␣ MAPK were derived from two studies. As reported previously (Li et al, 2004;Sweitzer et al, 2004), SD-282 demonstrates 14.3-fold selectivity for p38␣ MAPK (IC 50 values of 0.0016 and 0.0011 M) compared with p38␤ MAPK (IC 50 values of 0.023 and 0.022 M), whereas inhibition of p38␥ MAPK and p38␦ MAPK was less than 50%, even at concentrations of 10 M (Table 1). When tested in vitro at a concentration of 10 M, SD-282 demonstrated no inhibitory activity against a panel of other kinases, including extracellular signal-regulated kinase 2, c-Jun NH 2 -terminal kinase-1, and mitogen-activated protein kinase-activated protein kinase-2.…”

Differential astroglial responses in the spinal cord of rats submitted to a sciatic nerve double crush treated with local injection of cultured Schwann cell suspension or lesioned spinal cord extract: implications on cell therapy for nerve repair

“…Moreover, glial inhibitors exhibited anti-allodynic properties 13,14,43 . Furthermore, impairments of glial signaling by drugs that target glial activation 44 inhibited the synthesis and/or action of pro-inflammatory cytokines 45,46 and reduced neuropathic pain experimentally. Other evidences are related to the increased levels of prostaglandin E2 (PGE2) and COX2 in the spinal cord after peripheral infl ammation and neuropathic pain which might take place in local activated astrocytes.…”