School of Traditional Chinese Medicine, Southern Medical University, 1023-1063 Shatai South Road, Guangzhou 510515, China.
Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
Molecules. 2018 Sep 17;23(9):2370. doi: 10.3390/molecules23092370.
Sinomenine is a nonaddictive alkaloid used to prevent morphine dependence, even thoughits mechanism isnot fully understood. Astrocytes aggravate the pathological process in their neighboring cellsthrough exosomes in central nervous system diseases. However, the effect of sinomenine on astrocyte-derived exosomes for the amelioration of morphine dependence has not been reported yet. In this study, we found that sinomenine prevented the morphine-induced conditionedplace preference in mice. Sinomenine reduced the levels of cAMP and intracellular Ca in morphine-treated SH-SY5Y cells. Moreover, sinomenine inhibited the expressions of p-NMDAR1/NMDAR1, p-CAMKII/CAMKII, and p-CREB/CREB in the hippocampusof morphine-dependent mice and SH-SY5Y cells. Furthermore, we found that sinomenine inhibitedthe morphine-induced activation of astrocytesin vivo and in vitro. Afterwards, exosomes were isolated from cultured primary astrocytes treated with phosphate buffer saline (PBS, ctl-exo), morphine (mor-exo), or morphine and sinomenine (Sino-exo). Subsequently, morphine-treated SH-SY5Y cells were treated with ctl-exo, mor-exo, and Sino-exo. Results showed that Sino-exo reduced the level of cAMP, intracellular Ca, and the expression of p-CAMKII/CAMKII and p-CREB/CREB in morphine-treated SH-SY5Y cells. In conclusion, we demonstrated that sinomenine exhibited protective effects against morphine dependencein vivo and in vitro through theNMDAR1/CAMKII/CREB pathway. Sinomenine-induced alterationof the function of astrocyte-derived exosomes may contribute to the antidependence effects of sinomenine in morphine dependence.
青藤碱是一种用于预防吗啡依赖的非成瘾性生物碱，尽管其机制尚未完全阐明。星形胶质细胞通过细胞外囊泡在中枢神经系统疾病中加重其邻近细胞的病理过程。然而，青藤碱对星形胶质细胞衍生的外体改善吗啡依赖的作用尚未报道。在本研究中，我们发现青藤碱可预防小鼠吗啡诱导的条件性位置偏爱。青藤碱降低了吗啡处理的 SH-SY5Y 细胞中的 cAMP 和细胞内 Ca 水平。此外，青藤碱抑制了吗啡依赖小鼠和 SH-SY5Y 细胞中海马 p-NMDAR1/NMDAR1、p-CAMKII/CAMKII 和 p-CREB/CREB 的表达。此外，我们发现青藤碱抑制了体内和体外吗啡诱导的星形胶质细胞激活。之后，从用磷酸盐缓冲盐水 (PBS，ctl-exo)、吗啡 (mor-exo) 或吗啡和青藤碱 (Sino-exo) 处理的培养原代星形胶质细胞中分离出外体。随后，用 ctl-exo、mor-exo 和 Sino-exo 处理吗啡处理的 SH-SY5Y 细胞。结果表明，Sino-exo 降低了吗啡处理的 SH-SY5Y 细胞中的 cAMP、细胞内 Ca 水平以及 p-CAMKII/CAMKII 和 p-CREB/CREB 的表达。总之，我们证明青藤碱通过 NMDAR1/CAMKII/CREB 通路在体内和体外表现出对吗啡依赖的保护作用。青藤碱诱导的星形胶质细胞衍生的外体功能改变可能有助于青藤碱在吗啡依赖中的抗依赖作用。
