早期经鼓膜给药 rhBDNF 对顺铂诱导的听力损失具有多方面的神经保护作用。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-10-10 DOI:10.1111/bph.17359
Anna Pisani, Rolando Rolesi, Veronica Mohamed-Hizam, Raffaele Montuoro, Gaetano Paludetti, Cristina Giorgio, Pasquale Cocchiaro, Laura Brandolini, Nicola Detta, Anna Sirico, Pier Giorgio Amendola, Rubina Novelli, Andrea Aramini, Marcello Allegretti, Fabiola Paciello, Claudio Grassi, Anna Rita Fetoni
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引用次数: 0

摘要

背景和目的:顺铂诱导的感音神经性听力损失是一项重大的临床挑战。尽管此前已在一些耳毒性模型中研究了脑源性神经营养因子(BDNF)的潜在作用,但其对顺铂诱导的听力损失的疗效仍不确定。本研究旨在探讨重组人BDNF(rhBDNF)保护细胞免受顺铂诱导的耳毒性的治疗潜力:实验方法:我们使用顺铂诱导听力损失的体内模型,通过电生理学、形态学、免疫荧光和分子分析,研究了在热凝胶溶液中经鼓室给药rhBDNF对听力功能和耳蜗损伤的有益影响:我们的数据显示,通过保护耳蜗上皮的突触连接,保护毛细胞(HCs)和螺旋神经节神经元(SGNs)免受顺铂诱导的细胞死亡,局部rhBDNF治疗可抵消接受顺铂治疗的大鼠的听力损失。具体来说,rhBDNF 可维持其受体水平(pTrkB 和 p75)的平衡,增强 TrkB-CREB 的促生存信号,减少耳蜗中依赖于卡巴酶 3 的细胞凋亡。此外,它还能激活抗氧化机制,同时抑制炎症并促进血管修复:总之,我们证明了rhBDNF的早期经鼓室治疗对顺铂诱导的耳毒性具有多方面的保护作用,因此有望成为保护接受顺铂化疗的成人和儿童患者听力的一种新型潜在方法。
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Early transtympanic administration of rhBDNF exerts a multifaceted neuroprotective effect against cisplatin-induced hearing loss.

Background and purpose: Cisplatin-induced sensorineural hearing loss is a significant clinical challenge. Although the potential effects of brain-derived neurotrophic factor (BDNF) have previously been investigated in some ototoxicity models, its efficacy in cisplatin-induced hearing loss remains uncertain. This study aimed to investigate the therapeutic potential of recombinant human BDNF (rhBDNF) in protecting cells against cisplatin-induced ototoxicity.

Experimental approach: Using an in vivo model of cisplatin-induced hearing loss, we investigated the beneficial effects of transtympanic administration of rhBDNF in a thermogel solution on hearing function and cochlear injury, using electrophysiological, morphological, immunofluorescence and molecular analyses.

Key results: Our data showed that local rhBDNF treatment counteracted hearing loss in rats receiving cisplatin by preserving synaptic connections in the cochlear epithelium and protecting hair cells (HCs) and spiral ganglion neurons (SGNs) against cisplatin-induced cell death. Specifically, rhBDNF maintains the balance of its receptor levels (pTrkB and p75), boosting TrkB-CREB pro-survival signalling and reducing caspase 3-dependent apoptosis in the cochlea. Additionally, it activates antioxidant mechanisms while inhibiting inflammation and promoting vascular repair.

Conclusion and implications: Collectively, we demonstrated that early transtympanic treatment with rhBDNF plays a multifaceted protective role against cisplatin-induced ototoxicity, thus holding promise as a novel potential approach to preserve hearing in adult and paediatric patients undergoing cisplatin-based chemotherapy.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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