Therapeutic effects of nerve growth factor-targeting therapy on bladder overactivity in rats with prostatic inflammation.
Therapeutic effects of nerve growth factor-targeting therapy on bladder overactivity in rats with prostatic inflammation.
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DOI：
10.1002/pros.24227
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Yoshimura N
中科院分区：
文献类型：
--
作者：
Igarashi T;Tyagi P;Mizoguchi S;Saito T;Furuta A;Suzuki Y;Egawa S;Wang Z;Yoshimura N
本研究使用患有前列腺炎症（PI）的大鼠，检查了与神经生长因子反义寡核苷酸（NGF-OND）缀合的脂质体对 NGF 局部过度表达和膀胱过度活动的影响。雄性Sprague-Dawley大鼠分为三组：（1）对照组；完整大鼠，（2）PI-NS组； PI+膀胱灌注生理盐水(NS)大鼠，(3)PI-OND组；对大鼠进行 PI 和膀胱内滴注 NGF-OND。第0天，前列腺内注射5%福尔马林诱导PI。第14天，剖腹手术后将NGF-OND或NS直接滴入膀胱。第28天，通过清醒膀胱测量和组织学分析以及反转录聚合酶链反应测量膀胱和前列腺中NGF的信使RNA（mRNA）水平、前列腺中的炎症标记物、C纤维传入标记物以及L6-S1背根神经节（DRG）中的A型K+通道α亚基（Kv 1.4）来评估NGF-OND的治疗效果。膀胱内 NFG-OND 治疗减少了 PI 诱导的膀胱和前列腺中 NGF 的过度表达，并减少了 PI 诱导的膀胱过度活动，这明显表现为与 DRG 中 TRPV1 和 TRPA1 mRNA 表达水平降低相关的较长的收缩间隔。 PI后DRG中Kv1.4的mRNA表达降低，但PI-OND组中Kv1.4的mRNA表达有所改善。这些结果表明，膀胱局部表达的 NGF 是诱导膀胱过度活动的重要介质，PI 后 C 纤维传入标记物上调，DRG 中 A 型 K+ 通道亚基下调，基于脂质体的局部 NGF 靶向治疗不仅对膀胱过度活动和传入敏化有效，而且对 PI 也有效。因此，局部阻断膀胱中的 NGF 可能是治疗由 BPH 和 PI 引起的男性 LUTS 的一种治疗方式。
The present study examined the effect of liposomes conjugated with antisense oligonucleotide of nerve growth factor (NGF-OND) on local overexpression of NGF and bladder overactivity using rats with prostatic inflammation (PI). Male Sprague-Dawley rats were divided into three groups: (1) Control group; intact rats, (2) PI-NS group; rats with PI and intravesical instillation of normal saline (NS), (3) PI-OND group; rats with PI and intravesical instillation of NGF-OND. On Day 0, PI was induced by intraprostatic 5%-formalin injection. On Day 14, NGF-OND or NS was instilled directly into the bladder after laparotomy. On Day 28, therapeutic effects of NGF-OND were evaluated by awake cystometry and histological analysis as well as reverse-transcription polymerase chain reaction measurements of messenger RNA (mRNA) levels of NGF in the bladder and prostate, inflammatory markers in the prostate, C-fiber afferent markers, and an A-type K+ channel α-subunit (Kv 1.4) in L6-S1 dorsal root ganglia (DRG). Intravesical NFG-OND treatment reduced PI-induced overexpression of NGF in both bladder and prostate, and reduced PI-induced bladder overactivity evident as longer intercontraction intervals in association with reductions of TRPV1 and TRPA1 mRNA expression levels in DRG. mRNA expression of Kv1.4 in DRG was reduced after PI, but improved in the PI-OND group. These results indicate that NGF locally expressed in the bladder is an important mediator inducing bladder overactivity with upregulation of C-fiber afferent markers and downregulation of an A-type K+ channel subunit in DRG following PI, and that liposome-based, local NGF-targeting therapy could be effective for not only bladder overactivity and afferent sensitization, but also PI. Thus, local blockade of NGF in the bladder could be a therapeutic modality for male LUTS due to BPH with PI.
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