Inflammation-Independent Antinociceptive Effects of DF2755A, a CXCR1/2 Selective Inhibitor: A New Potential Therapeutic Treatment for Peripheral Neuropathy Associated to Non-Ulcerative Interstitial Cystitis/Bladder Pain Syndrome.
Inflammation-Independent Antinociceptive Effects of DF2755A, a CXCR1/2 Selective Inhibitor: A New Potential Therapeutic Treatment for Peripheral Neuropathy Associated to Non-Ulcerative Interstitial Cystitis/Bladder Pain Syndrome.
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DOI：
10.3389/fphar.2022.854238
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发表时间：
2022
影响因子：
5.6
通讯作者：
Allegretti, Marcello
中科院分区：
文献类型：
--
作者：
Brandolini, Laura;Aramini, Andrea;Bianchini, Gianluca;Ruocco, Anna;Bertini, Riccardo;Novelli, Rubina;Angelico, Patrizia;Valsecchi, Anna Elisa;Russo, Roberto;Castelli, Vanessa;Cimini, Annamaria;Allegretti, Marcello
关键词：
间质性膀胱炎(IC)/膀胱疼痛综合征(BPS)是一种病因不明的慢性膀胱疾病，以尿频、阵发性和慢性疼痛为特征。IC/BPS的止痛治疗是有限的，尤其是对于非溃疡型IC患者，他们的总体结果通常很差。在这里，我们证明了口服DF2755A，一种有效的和选择性的趋化因子受体CXCR1/2抑制剂，可以通过直接抑制趋化因子诱导的感觉神经元的兴奋来预防和逆转与非HUNNER IC/BPS相关的周围神经病。我们在环磷酰胺(CYP)诱导的非溃疡性IC大鼠模型上测试了DF2755A的抗伤害性作用，该模型的特征是严重的周围神经病变，没有膀胱炎性浸润物、尿路上皮增生和出血。DF2755A可预防CYP诱导的IC大鼠周围神经病变的发生并逆转其发展，显示出强烈而持久的抗痛觉过敏作用。体外和体外研究表明，与载体相比，DF2755A对CXCR2激动剂CXCL1/KC和CXCL5以及瞬时受体电位香草素1(TRPV1)的表达有强烈的抑制作用，提示其作用可能是通过抑制通过CXCL1/CXCR1-2轴和TRPV1的伤害性信号而实现的。总之，我们的结果强调了CXCL1/CXCR1-2轴和TRPV1在非HUNNER IC周围神经病的发生和发展中所起的关键病理生理学作用，并建议DF2755A不仅是一种潜在的治疗方法，不仅可以治疗炎性疼痛，也可以治疗神经病理性疾病，特别是非HUNNER IC/BPS。
Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hyperalgesic effect. Ex vivo and in vitro studies showed that DF2755A treatment strongly inhibited the expression of CXCR2 agonists, CXCL1/KC, and CXCL5 and of transient receptor potential vanilloid 1 (TRPV1) compared to vehicle, suggesting that its effects can be due to the inhibition of the nociceptive signaling passing through the CXCL1/CXCR1-2 axis and TRPV1. In conclusion, our results highlight the key pathophysiological role played by the CXCL1/CXCR1-2 axis and TRPV1 in the onset and development of peripheral neuropathy in non-Hunner IC and propose DF2755A as a potential therapeutic approach for the treatment of not only inflammatory painful conditions but also neuropathic ones and in particular non-Hunner IC/BPS.
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趋化因子 CXCL1 通过激活 CXCR2 增强脊髓神经元中的炎性疼痛并增加 NMDA 受体活性和 COX-2 表达
影响因子：
5.3
作者：
Cao, De-Li;Zhang, Zhi-Jun;Xie, Rou-Gang;Jiang, Bao-Chun;Ji, Ru-Rong;Gao, Yong-Jing
通讯作者：
Gao, Yong-Jing
影响因子：
2
作者：
Gupta P;Gaines N;Sirls LT;Peters KM
通讯作者：
Peters KM
影响因子：
6.6
作者：
Clemens, JQ;Meenan, RT;Calhoun, EA
通讯作者：
Calhoun, EA
影响因子：
--
作者：
Brandolini L;Benedetti E;Ruffini PA;Russo R;Cristiano L;Antonosante A;d'Angelo M;Castelli V;Giordano A;Allegretti M;Cimini A
通讯作者：
Cimini A
DOI：
10.1111/febs.14466
发表时间：
2018-08
期刊：
The FEBS journal
影响因子：
--
作者：
Hughes CE;Nibbs RJB
通讯作者：
Nibbs RJB