Tong Yat-Ching, Cheng Juei-Tang
Departments of Urology and Pharmacology, School of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
J Urol. 2007 Nov;178(5):2203-7. doi: 10.1016/j.juro.2007.06.048. Epub 2007 Sep 17.
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.
我们使用链脲佐菌素（Sigma公司）诱导的糖尿病大鼠模型，评估醛糖还原酶抑制剂ONO - 2235（中国化学制药公司，台北，台湾）对糖尿病相关的膀胱神经生长因子及神经生长因子神经营养素受体p75 mRNA表达变化的治疗效果。
雄性Wistar大鼠分为3组，包括第1组——用赋形剂处理的正常大鼠，第2组——用赋形剂处理的9周龄链脲佐菌素糖尿病大鼠，以及第3组——用ONO - 2235处理的9周龄链脲佐菌素糖尿病大鼠。使用麻醉进行体内膀胱内压测量。通过酶联免疫吸附测定法测量膀胱神经生长因子水平。使用逆转录 - 聚合酶链反应研究大鼠膀胱中编码神经生长因子和神经营养素受体p75的mRNA表达。
膀胱内压测量显示糖尿病大鼠膀胱容量增加且排空功能降低。ONO - 2235治疗改善了排尿量、排尿分数和残余尿量。在每组8次实验中，链脲佐菌素诱导的糖尿病大鼠膀胱中的神经生长因子浓度显著低于对照水平（分别为平均±标准误45.78±4.36和96.44±8.73 pg/μg蛋白质，p<0.01）。在每组8次实验中，糖尿病大鼠膀胱神经生长因子和神经营养素受体p75的mRNA表达与对照相比均显著降低（分别为p<0.01和<0.001）。用ONO - 2235治疗未显著改变糖尿病大鼠的血糖水平。然而，在每组8次实验中，给予该药物均显著提高了膀胱神经生长因子浓度以及神经生长因子mRNA和神经营养素受体p75 mRNA表达至正常水平（分别为p<0.01、<0.01和<0.001）。
ONO - 2235改善了9周龄链脲佐菌素诱导的糖尿病大鼠的膀胱排空功能，并恢复了膀胱神经生长因子和神经营养素受体p75降低的基因表达，表明山梨醇途径参与了糖尿病膀胱病期间神经生长因子和p75（NTR）的基因下调。
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