CB2 receptor agonists protect human dopaminergic neurons against damage from HIV-1 gp120.
CB2 receptor agonists protect human dopaminergic neurons against damage from HIV-1 gp120.
复制标题
DOI：
10.1371/journal.pone.0077577
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rock RB
中科院分区：
文献类型：
--
作者：
Hu S;Sheng WS;Rock RB
尽管抗逆转录病毒疗法的治疗效果，HIV-1相关的神经认知障碍（HAND）仍然是对艾滋病患者的严重威胁，目前仍然没有针对HIV-1神经学表现的特异性治疗。最近的工作表明，黑质纹状体多巴胺能区是一个关键的大脑区域的神经元功能障碍和死亡中看到的手和人类多巴胺能神经元有一个特殊的敏感性gp 120诱导的损害，表现为减少功能（减少多巴胺摄取），形态学变化，并降低生存能力。合成大麻素抑制人类小胶质细胞中的HIV-1表达，抑制人类星形胶质细胞中炎症介质的产生，并且有大量文献证明大麻素在其他神经病理过程中的神经保护特性。基于这些数据，设计实验来检验合成大麻素将保护多巴胺能神经元免受HIV-1蛋白gp 120的毒性作用的假设。使用人中脑神经元/神经胶质细胞培养模型，其中含有多巴胺能神经元，小胶质细胞和星形胶质细胞，我们能够表明，CB 1/CB 2激动剂WIN 55，212-2钝化gp 120诱导的神经元损伤，通过多巴胺转运蛋白功能，细胞凋亡和脂质过氧化作用，这些行动主要是由CB 2受体介导的。向我们的培养物中添加补充的人类小胶质细胞增强了gp 120诱导的损伤; WIN 55，212-2能够减轻这种增强的损伤。此外，WIN 55，212-2抑制纯化的人小胶质细胞产生gp 120诱导的超氧化物，抑制人小胶质细胞向gp 120刺激的人中脑神经元/胶质细胞培养物产生的上清液迁移，并减少人中脑神经元/胶质细胞培养物产生的趋化因子和细胞因子。这些数据表明，合成大麻素能够以多种方式保护人类多巴胺能神经元免受gp 120的影响，主要通过CB 2受体和小胶质细胞起作用。
Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake), morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120-induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia.
登录
查看更多内容
影响因子：
4.7
作者：
Choi, SH;Lee, DY;Jin, BK
通讯作者：
Jin, BK
影响因子：
3.5
作者：
AURIAULT, C;JOSEPH, M;CAPRON, A
通讯作者：
CAPRON, A
DOI：
10.1006/bbrc.2000.3160
发表时间：
2000-08-11
影响因子：
3.1
作者：
Corasaniti, MT;Strongoli, MC;Bagetta, G
通讯作者：
Bagetta, G
DOI：
10.2174/187153008785700118
发表时间：
2008-09-01
影响因子：
1.9
作者：
Cabral, G. A.;Griffin-Thomas, L.
通讯作者：
Griffin-Thomas, L.
DOI：
10.1016/0192-0561(85)90011-6
发表时间：
1985-01-01
期刊：
INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY
影响因子：
--
作者：
AURIAULT, C;JOSEPH, M;CAPRON, A
通讯作者：
CAPRON, A