Protective effect of a novel phosphodiesterase 4 selective inhibitor, compound A, in diabetic nephropathy model mice.

Protective effect of a novel phosphodiesterase 4 selective inhibitor, compound A, in diabetic nephropathy model mice. Eur J Pharmacol. 2021 Jan 07;:173852 Authors: Ookawara M, Nio Y, Yamasaki M, Kuniyeda K, Hanauer G, Tohyama K, Hazama M, Matsuo T Abstract Phosphodiesterase subtype 4 (PDE4) hydrolyzes cyclic AMP (cAMP), a secondary messenger that mediates intracellular signaling, and plays key roles in inflammatory and profibrotic responses. Clinical benefits of pentoxifylline, a non-selective PDE inhibitor, have been reported in patients with kidney disease. Here, we identified compound A as a potent and selective PDE4 inhibitor and evaluated its potential as a novel therapeutic agent for diabetic nephropathy (DN). To determine its in vivo efficacy on DN, uninephrectomized (UNx-) db/db mice and KKAy mice were used as DN mice models. Eight-week repeated dosing with compound A (1-10 mg/kg, QD, p.o.) showed dose-dependent and significant suppressive effects on glycosylated hemoglobin (GHb) and urinary albumin/creatinine ratio (UACR) in UNx-db/db mice. These effects are more potent than irbesartan, a clinically approved angiotensin II receptor blocker of DN. Moreover, compound A suppressed pro-fibrotic and pro-inflammatory marker mRNAs and increased anti-reactive oxygen species marker mRNAs in the kidneys of UNx-db/db mice. The similar effect of compound A on UACR was also demonstrated by 8-week repeated dose in KKAy mice, another model...
Source: European Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharmacol Source Type: research