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Effect of acute and subchronic administration of (R)-WIN55,212-2 induced neuroprotection and anti inflammatory actions in rat retina: CB1 and CB2 receptor involvement
Neurochemistry international ( IF 4.2 ) Pub Date : 2020-11-19 , DOI: 10.1016/j.neuint.2020.104907
Dimitris Spyridakos 1 , Sofia Papadogkonaki 1 , Stavroula Dionysopoulou 1 , Niki Mastrodimou 1 , Hara Polioudaki 2 , Kyriaki Thermos 1
Affiliation  

Cannabinoids have been shown to protect the retina from ischemic/excitotoxic insults. The aim of the present study was to investigate the neuroprotective and anti-inflammatory properties of the synthetic cannabinoid (R)-WIN55,212-2 (CB1/CB2 receptor agonist) when administered acutely or subchronically in control and AMPA treated retinas. Sprague-Dawley rats were intravitreally administered (acutely) with vehicle or AMPA, in the absence or presence of (R)-WIN55,212-2 (10−7-10−4M) alone or in combination with AM251 [CB1 receptor antagonist/inverse agonist,10−4M] and AM630 (CB2 receptor antagonist,10−4M). In addition, AMPA was co-administered with the racemic (R,S)-WIN55,212 (10−4Μ). (R)-WIN55,212-2 was also administered subchronically (25,100 μg/kg,i.p.,4d) in control and AMPA treated rats. Immunohistochemical studies were performed using antibodies against the CB1R, and retinal markers for retinal neurons (brain nitric oxide synthetase, bNOS) and microglia (ionized calcium binding adaptor molecule 1, Iba1). ELISA assay was employed to assess TNFα levels in AMPA treated retinas. Intravitreal administration of (R)-WIN55,212-2 reversed the AMPA induced loss of bNOS expressing amacrine cells, an effect that was blocked by both AM251 and AM630. (R,S)WIN55,212 had no effect. (R)-WIN55,212-2 also reduced a) the AMPA induced activation of microglia, by activating CB2 receptors that were shown to be colocalized with Iba1+ reactive microglial cells, and b) TNFα levels in retina. (R)-WIN55,212-2 administered subchronically led to the downregulation of CB1 receptors at the high dose of 100 μg/kg(i.p.), and to the attenuation of the WIN55,212-2 induced neuroprotection of amacrine cells. At the same dose, (R)-WIN55,212-2 did not attenuate the AMPA induced increase in the number of reactive microglia cells, suggesting CB2 receptor downregulation under subchronic conditions. This study provides new findings regarding the role of CB1 and CB2 receptor activation by the synthetic cannabinoid (R)-WIN55,212-2, administered acutely or sub-chronically, on neuron viability and microglia activation in healthy and diseased retina.



中文翻译:

(R)-WIN55,212-2 的急性和亚慢性给药对大鼠视网膜神经保护和抗炎作用的影响:CB1 和 CB2 受体参与

大麻素已被证明可以保护视网膜免受缺血性/兴奋性毒性的侵害。本研究的目的是研究合成大麻素 (R)-WIN55,212-2(CB1/CB2 受体激动剂)在对照和 AMPA 处理的视网膜中急性或亚慢性给药时的神经保护和抗炎特性。在不存在或存在 (R)-WIN55,212-2 (10 -7 -10 -4 M) 单独或与 AM251 [CB1 受体拮抗剂/反向激动剂,10 -4 M]和AM630(CB2受体拮抗剂,10 -4 M)。此外,AMPA 与外消旋 (R,S)-WIN55,212 (10 -4M)。(R)-WIN55,212-2 还在对照和 AMPA 治疗的大鼠中亚慢性给药 (25,100 μg/kg,ip,4d)。使用针对 CB1R 的抗体和视网膜神经元(脑一氧化氮合成酶,bNOS)和小胶质细胞(离子钙结合接头分子 1,Iba1)的视网膜标记物进行免疫组织化学研究。采用ELISA测定来评估AMPA处理的视网膜中的TNFα水平。(R)-WIN55,212-2 的玻璃体内给药逆转了 AMPA 诱导的 bNOS 表达无长突细胞的丢失,这种作用被 AM251 和 AM630 阻断。(R,S)WIN55,212 没有效果。(R)-WIN55,212-2 还减少了 a) AMPA 诱导的小胶质细胞激活,通过激活与 Iba1 +共定位的 CB2 受体反应性小胶质细胞,和 b) 视网膜中的 TNFα 水平。(R)-WIN55,212-2 亚慢性给药导致 CB1 受体在 100 μg/kg(ip) 的高剂量下下调,并减弱 WIN55,212-2 诱导的无长突细胞神经保护作用。在相同剂量下,(R)-WIN55,212-2 不会减弱 AMPA 诱导的反应性小胶质细胞数量的增加,表明亚慢性条件下 CB2 受体下调。这项研究提供了关于合成大麻素 (R)-WIN55,212-2 激活 CB1 和 CB2 受体的新发现,急性或亚慢性给药对健康和患病视网膜中神经元活力和小胶质细胞激活的影响。

更新日期:2020-11-22
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