The cannabinoid CB2 receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis
The cannabinoid CB2 receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis
复制标题
DOI：
10.1111/bph.12478
复制
发表时间：
2014-01-01
影响因子：
7.3
通讯作者：
Avraham, Shalom
中科院分区：
文献类型：
--
作者：
Avraham, Hava Karsenty;Jiang, Shuxian;Avraham, Shalom
背景与目的hiv -1糖蛋白Gp120在体外和体内诱导鼠类和人神经元凋亡。在胶质纤维酸性蛋白(GFAP)/Gp120转基因（Tg）小鼠中，HIV-1/Gp120参与hiv相关痴呆（HAD）的发病机制，并抑制成体神经祖细胞（npc）的增殖。由于大麻素在几种模型系统中发挥神经保护作用，我们研究了CB2受体激动剂AM1241对gp120介导的神经发生损伤的保护作用。实验方法采用免疫组织化学和TUNEL技术评估AM1241对人和鼠NPCs细胞存活和凋亡的影响。免疫组织化学方法观察GFAP/Gp120转基因小鼠海马神经发生情况。sam1241在体外抑制rogp120介导的人、鼠原代npc的神经毒性和凋亡，提高其存活率。AM1241也能促进npc向神经元细胞的分化。GFAP/Gp120 Tg小鼠表现出神经发生受损，表现为BrdU（+）细胞和双皮质素（+）（DCX+）细胞减少，增殖细胞核抗原（PCNA）细胞减少，而给药GFAP/Gp120 Tg小鼠AM1241导致海马体内神经发生增强，表现为神经母细胞、神经元细胞、BrdU（+）细胞和PCNA（+）细胞增加。与载药组相比，AM1241可减少GFAP/Gp120 Tg小鼠的星形胶质细胞形成和胶质细胞形成。结论和意义CB2受体激动剂可挽救HIV-1/Gp120损伤引起的神经发生受损。因此，CB2受体激动剂可能作为神经保护剂，恢复HAD患者受损的神经发生。
Background and PurposeHIV-1 glycoprotein Gp120 induces apoptosis in rodent and human neurons in vitro and in vivo.HIV-1/Gp120 is involved in the pathogenesis of HIV-associated dementia (HAD) and inhibits proliferation of adult neural progenitor cells (NPCs) in glial fibrillary acidic protein (GFAP)/Gp120 transgenic (Tg) mice. As cannabinoids exert neuroprotective effects in several model systems, we examined the protective effects of the CB2 receptor agonist AM1241 on Gp120-mediated insults on neurogenesis.Experimental ApproachWe assessed the effects of AM1241 on survival and apoptosis in cultures of human and murine NPCs with immunohistochemical and TUNEL techniques. Neurogenesis in the hippocampus of GFAP/Gp120 transgenic mice in vivo was also assessed by immunohistochemistry.Key ResultsAM1241 inhibited in vitroGp120-mediated neurotoxicity and apoptosis of primary human and murine NPCs and increased their survival. AM1241 also promoted differentiation of NPCs to neuronal cells. While GFAP/Gp120 Tg mice exhibited impaired neurogenesis, as indicated by reduction in BrdU(+) cells and doublecortin(+) (DCX+) cells, and a decrease in cells with proliferating cell nuclear antigen (PCNA), administration of AM1241 to GFAP/Gp120 Tg mice resulted in enhanced in vivo neurogenesis in the hippocampus as indicated by increase in neuroblasts, neuronal cells, BrdU(+) cells and PCNA(+) cells. Astrogliosis and gliogenesis were decreased in GFAP/Gp120 Tg mice treated with AM1241, compared with those treated with vehicle.Conclusions and ImplicationsThe CB2 receptor agonist rescued impaired neurogenesis caused by HIV-1/Gp120 insult. Thus, CB2 receptor agonists may act as neuroprotective agents, restoring impaired neurogenesis in patients with HAD.