The Endocannabinoid/Cannabinoid Receptor 2 System Protects Against Cisplatin-Induced Hearing Loss.
The Endocannabinoid/Cannabinoid Receptor 2 System Protects Against Cisplatin-Induced Hearing Loss.
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DOI：
10.3389/fncel.2018.00271
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发表时间：
2018
影响因子：
5.3
通讯作者：
Ramkumar V
中科院分区：
文献类型：
--
作者：
Ghosh S;Sheth S;Sheehan K;Mukherjea D;Dhukhwa A;Borse V;Rybak LP;Ramkumar V
以往的研究表明，大麻素2受体（CB 2 R）的存在，这是由顺铂诱导的大鼠耳蜗。在Corti器官衍生的细胞培养模型中，还显示CB 2 R的激动剂保护这些细胞免受顺铂诱导的细胞凋亡。在目前的研究中，我们确定了CB 2 R在小鼠和大鼠耳蜗中的分布，并检查这些受体是否对顺铂诱导的听力损失提供保护。在表达绿色荧光蛋白标记的CB 2 R的敲入小鼠模型中，我们显示CB 2 R在Corti器官、血管纹、螺旋韧带和螺旋神经节细胞中的分布。使用CB 2 R的多克隆抗体在大鼠耳蜗中观察到CB 2 R的类似分布。经鼓膜给予CB 2 R的选择性激动剂（2-甲基-1-丙基-1H-吲哚-3-基）-1-萘甲酮（JWH 015），可防止顺铂诱导的听力损失，并可通过CB 2 R拮抗剂6-碘-2-甲基-1-[2-（4-吗啉基）乙基]-1H-吲哚-3-基]（4-甲氧基苯基）甲酮（AM 630）阻断该受体而逆转。JWH 015还减少Corti器官中的外毛细胞（OHC）的损失、内毛细胞（IHC）带状突触的损失和血管纹中Na+/K+-ATP酶免疫反应性的损失。AM 630单独给药产生显著的听力损失（通过听觉脑干反应测量），这与OHC的损失无关，但导致IHC带状突触和CaNa +/K+-ATP酶免疫反应性水平降低。此外，通过经鼓室施用siRNA敲低CB 2 R使耳蜗对顺铂诱导的低频和中频听力损失敏感。顺铂和AM 630诱导的大鼠听力损失与大鼠耳蜗中氧化应激和炎症蛋白基因表达增加有关。体外研究表明，JWH 015不会改变顺铂诱导的癌细胞杀伤作用，表明该药物可安全用于顺铂化疗。这些数据揭示了耳蜗内源性大麻素/CB 2 R系统的保护作用，该系统在正常条件下表现为强直活性以保持正常听力。然而，需要一种外源性激动剂来增强内源性大麻素/CB 2 R系统的活性，以保护免受更具创伤性的耳蜗损伤，如顺铂给药所观察到的。
Previous studies have demonstrated the presence of cannabinoid 2 receptor (CB2R) in the rat cochlea which was induced by cisplatin. In an organ of Corti-derived cell culture model, it was also shown that an agonist of the CB2R protected these cells against cisplatin-induced apoptosis. In the current study, we determined the distribution of CB2R in the mouse and rat cochleae and examined whether these receptors provide protection against cisplatin-induced hearing loss. In a knock-in mouse model expressing the CB2R tagged with green fluorescent protein, we show distribution of CB2R in the organ of Corti, stria vascularis, spiral ligament and spiral ganglion cells. A similar distribution of CB2R was observed in the rat cochlea using a polyclonal antibody against CB2R. Trans-tympanic administration of (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH015), a selective agonist of the CB2R, protected against cisplatin-induced hearing loss which was reversed by blockade of this receptor with 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630), an antagonist of CB2R. JWH015 also reduced the loss of outer hair cells (OHCs) in the organ of Corti, loss of inner hair cell (IHC) ribbon synapses and loss of Na+/K+-ATPase immunoreactivity in the stria vascularis. Administration of AM630 alone produced significant hearing loss (measured by auditory brainstem responses) which was not associated with loss of OHCs, but led to reductions in the levels of IHC ribbon synapses and strial Na+/K+-ATPase immunoreactivity. Furthermore, knock-down of CB2R by trans-tympanic administration of siRNA sensitized the cochlea to cisplatin-induced hearing loss at the low and middle frequencies. Hearing loss induced by cisplatin and AM630 in the rat was associated with increased expression of genes for oxidative stress and inflammatory proteins in the rat cochlea. In vitro studies indicate that JWH015 did not alter cisplatin-induced killing of cancer cells suggesting this agent could be safely used during cisplatin chemotherapy. These data unmask a protective role of the cochlear endocannabinoid/CB2R system which appears tonically active under normal conditions to preserve normal hearing. However, an exogenous agonist is needed to boost the activity of endocannabinoid/CB2R system for protection against a more traumatic cochlear insult, as observed with cisplatin administration.
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影响因子：
4.8
作者：
Blázquez, C;Casanova, ML;Guzmán, M
通讯作者：
Guzmán, M
短暂干扰RNA对STAT1的干扰可通过抑制炎症来减弱顺铂诱导的大鼠耳毒性。
影响因子：
9
作者：
通讯作者：
--
影响因子：
3.5
作者：
Laezza, Chlara;Pisanti, Simona;Bifulco, Maurizio
通讯作者：
Bifulco, Maurizio
影响因子：
3.3
作者：
Lallemend, F.;Vandenbosch, R.;Malgrange, B.
通讯作者：
Malgrange, B.
DOI：
10.1523/jneurosci.2845-09.2009
发表时间：
2009-11-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kujawa SG;Liberman MC
通讯作者：
Liberman MC