Background: p38 signaling pathway plays a key role in inflammatory diseases. Results: A single copy disruption of the p38␣ gene or a p38␣ inhibitor markedly reduced the pathogenesis of EAE by decreasing IL-17 production. Conclusion: p38␣ regulates the pathogenesis of EAE through transcriptional regulation of IL-17 production. Significance: Anti-p38␣ strategy achieves therapeutic benefit for the treatment of multiple sclerosis.

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The pharmacological profiles of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) were investigated in terms of hog gastric H ϩ ,K ϩ -ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in comparison with other proton pump inhibitors (PPIs). CS-526 inhibited H ϩ ,K ϩ -ATPase activity in a concentration-dependent manner, with an IC 50 value of 61 nM. The inhibitory effect of CS-526 on H ϩ ,K ϩ -ATPase activity was more potent than that of any of the other PPIs examined. The inhibitory mechanism of CS-526 on H ϩ ,K ϩ -ATPase was a competitive antagonism to the K ϩ binding site of H ϩ ,K ϩ -ATPase, and it was also a reversible inhibition. In pylorus-ligated rats, intraduodenal or oral administration of CS-526 inhibited gastric acid secretion in a dose-dependent manner, and the ID 50 values were 2.8 or 0.7 mg/kg, respectively. In Heidenhain pouch dogs, intrapouch administration of CS-526 inhibited histamine-stimulated gastric acid secretion in a dose-and retention time-dependent manner. In a reflux esophagitis model, intraduodenal and oral administration of CS-526 prevented esophageal lesions with ID 50 values of 5.4 and 1.9 mg/kg, respectively. Lansoprazole prevented esophagitis only by intraduodenal administration (ID 50 ϭ 2.2 mg/kg). Furthermore, CS-526 inhibited acute gastric mucosal lesions. These data demonstrate that the novel acid pump antagonist CS-526 has potent antisecretory and antiulcer effects. These findings indicate that CS-526 would have a curative effect on gastroesophageal reflux disease via its potent antisecretory and antiulcer actions.

In the present report, we evaluated the effect of the novel acid pump antagonist 7-

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