Department of Anatomy and Neurobiology, University of Vermont, Burlington, VT 05405, USA.
J Mol Neurosci. 2012 Nov;48(3):730-43. doi: 10.1007/s12031-012-9834-1. Epub 2012 Jun 15.
We have previously demonstrated nerve growth factor (NGF) regulation of pituitary adenylate cyclase-activating polypeptide (PACAP)/receptors in bladder reflex pathways using a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelial-specific uroplakin II promoter. We have now explored the contribution of target-derived NGF in combination with cyclophosphamide (CYP)-induced cystitis to determine whether additional changes in neuropeptides/receptors are observed in micturition reflex pathways due to the presence of additional inflammatory mediators in the urinary bladder. Quantitative PCR was used to determine PACAP/vasoactive intestinal polypeptide (VIP), substance P, galanin, and receptor transcript expression in the urinary bladder (urothelium, detrusor) in mice with overexpression of NGF in the urothelium (NGF-OE) and wild-type (WT) mice with CYP-induced cystitis (4 h, 48 h, and chronic). With CYP-induced cystitis (4 h), WT and NGF-OE mice exhibited similar changes in galanin transcript expression in the urothelium (30-fold increase) and detrusor (threefold increase). In contrast, PACAP, VIP, and substance P transcripts exhibited differential changes in WT and NGF-OE with CYP-induced cystitis. PAC1, VPAC1, and VPAC2 transcript expression also exhibited differential responses in NGF-OE mice that were tissue (urothelium vs. detrusor) and CYP-induced cystitis duration-dependent. Using conscious cystometry, NGF-OE mice treated with CYP exhibited significant (p ≤ 0.01) increases in voiding frequency above that observed in control NGF-OE mice. In addition, no changes in the electrical properties of the major pelvic ganglia neurons of NGF-OE mice were detected using intracellular recording, suggesting that the urinary bladder phenotype in NGF-OE mice is not influenced by changes in the efferent limb of the micturition reflex. These studies are consistent with target-derived NGF and other inflammatory mediators affecting neurochemical plasticity and the reflex function of micturition pathways.
我们之前已经使用膀胱上皮特异性尿路上皮蛋白 II 启动子在膀胱中过表达神经生长因子 (NGF) 的转基因小鼠模型证明了 NGF 对膀胱反射途径中垂体腺苷酸环化酶激活肽 (PACAP)/受体的调节作用。现在，我们已经探索了靶源性 NGF 与环磷酰胺 (CYP) 诱导的膀胱炎的联合作用，以确定由于在膀胱中存在额外的炎症介质，是否会在排尿反射途径中观察到神经肽/受体的额外变化。定量 PCR 用于确定过表达 NGF 的尿路上皮 (NGF-OE) 和野生型 (WT) 小鼠的膀胱 (尿路上皮、逼尿肌) 中 PACAP/血管活性肠肽 (VIP)、P 物质、甘丙肽和受体转录表达，用 CYP 诱导膀胱炎 (4 h、48 h 和慢性)。用 CYP 诱导膀胱炎 (4 h)，WT 和 NGF-OE 小鼠的尿路上皮 (30 倍增加) 和逼尿肌 (三倍增加) 甘丙肽转录表达均发生类似变化。相比之下，在 WT 和 NGF-OE 中，PACAP、VIP 和 P 物质转录在 CYP 诱导的膀胱炎中表现出不同的变化。PAC1、VPAC1 和 VPAC2 转录表达也在 NGF-OE 小鼠中表现出组织 (尿路上皮与逼尿肌) 和 CYP 诱导的膀胱炎持续时间依赖性的差异反应。使用清醒的膀胱测压法，用 CYP 处理的 NGF-OE 小鼠的排尿频率显著增加 (p≤0.01)，高于对照 NGF-OE 小鼠。此外，在使用细胞内记录的 NGF-OE 小鼠的主要盆神经节神经元的电特性中未检测到变化，这表明 NGF-OE 小鼠的膀胱表型不受排尿反射传出支变化的影响。这些研究与靶源性 NGF 和其他炎症介质影响神经化学可塑性和排尿途径反射功能的研究一致。
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