Aldose Reductase Inhibitor ONO-2235 Restores the Alterations of Bladder Nerve Growth Factor and Neurotrophin Receptor p75 Genetic Expression in Streptozotocin Induced Diabetic Rats

Abstract

We assessed the treatment effect of the aldose reductase inhibitor ONO-2235 (China Chemical and Pharmaceutical, Taipei, Taiwan) on diabetes associated alterations in bladder nerve growth factor and the nerve growth factor neurotrophin receptor p75 mRNA expressions using the streptozotocin (Sigma) induced diabetic rat model. Male Wistar rats were divided into 3 groups, including group 1--vehicle treated normal rats, group 2--vehicle treated 9-week streptozotocin diabetic rats and group 3--ONO-2235 treated 9-week streptozotocin diabetic rats. In vivo cystometry was performed using anesthesia. Bladder nerve growth factor levels were measured by enzyme linked immunosorbent assay. Expression of the mRNA encoding nerve growth factor and neurotrophin receptor p75 in the rat bladder was studied using reverse transcriptase-polymerase chain reaction. Cystometry showed increased bladder capacity and decreased emptying function in diabetic rats. ONO-2235 treatment improved voiding volume, voiding fraction and residual volume. The nerve growth factor concentration in streptozotocin induced diabetic rat bladders was significantly lower than the control level in 8 experiments each (mean +/- SEM 45.78 +/- 4.36 and 96.44 +/- 8.73 pg/microg protein, respectively, p <0.01). The mRNA expression of bladder nerve growth factor and neurotrophin receptor p75 in diabetic rats was significantly decreased compared to that in controls in 8 experiments each (p <0.01 and <0.001, respectively). Treatment with ONO-2235 did not significantly change the blood sugar level in diabetic rats. However, administration of the drug significantly increased the bladder nerve growth factor concentration as well as nerve growth factor mRNA and neurotrophin receptor p75 mRNA expression to normal levels in 8 experiments each (p <0.01, <0.01 and <0.001, respectively). ONO-2235 improved bladder emptying function and restored the decreased genetic expression of bladder nerve growth factor and neurotrophin receptor p75 in 9-week streptozotocin induced diabetic rats, indicating involvement of the sorbitol pathway in the genetic down-regulations of nerve growth factor and p75(NTR) during diabetic cystopathy.