Lisak Robert P, Nedelkoska Liljana, Benjamins Joyce A
Department of Neurology, Wayne State University School of Medicine, 3122 Elliman Building, 421 E. Canfield Ave., Detroit, MI 48201, United States.
Department of Neurology, Wayne State University School of Medicine, 3122 Elliman Building, 421 E. Canfield Ave., Detroit, MI 48201, United States.
J Neurol Sci. 2016 Mar 15;362:21-6. doi: 10.1016/j.jns.2016.01.009. Epub 2016 Jan 7.
Damage to myelin and oligodendroglia (OL) in multiple sclerosis (MS) results from a wide array of mechanisms including excitotoxicity, neuroinflammation and oxidative stress. We previously showed that ACTH 1-39, a melanocortin, protects OL in mixed glial cultures and enriched OL cultures, inhibiting OL death induced by staurosporine, ionotropic glutamate receptors, quinolinic acid or reactive oxygen species (ROS), but not nitric oxide (NO) or kynurenic acid. OL express melanocortin receptor 4 (MC4R), suggesting a direct protective effect of ACTH 1-39 on OL. However, these results do not rule out the possibility that astroglia (AS) or microglia (MG) also play roles in protection. To investigate this possibility, we prepared conditioned medium (CM) from AS and MG treated with ACTH, then assessed the protective effects of the CM on OL. CM from AS treated with ACTH protected OL from glutamate, NMDA, AMPA, quinolinic acid and ROS but not from kainate, staurosporine, NO or kynurenic acid. CM from MG treated with ACTH did not protect from any of these molecules, nor did CM from AS or MG not treated with ACTH. While protection of OL by ACTH from several toxic molecules involves direct effects on OL, ACTH can also stimulate AS to produce mediators that protect against some molecules but not others. Thus the cellular mechanisms underlying the protective effects of ACTH for OL are complex, varying with the toxic molecules.
多发性硬化症（MS）中髓鞘和少突胶质细胞（OL）的损伤源于多种机制，包括兴奋性毒性、神经炎症和氧化应激。我们之前表明，促肾上腺皮质激素1-39（一种促黑素皮质素）在混合胶质细胞培养物和富集的OL培养物中可保护OL，抑制由星形孢菌素、离子型谷氨酸受体、喹啉酸或活性氧（ROS）诱导的OL死亡，但对一氧化氮（NO）或犬尿烯酸无效。OL表达促黑素皮质素受体4（MC4R），提示促肾上腺皮质激素1-39对OL有直接保护作用。然而，这些结果并未排除星形胶质细胞（AS）或小胶质细胞（MG）也在保护过程中发挥作用的可能性。为了研究这种可能性，我们制备了用促肾上腺皮质激素处理的AS和MG的条件培养基（CM），然后评估CM对OL的保护作用。用促肾上腺皮质激素处理的AS的CM可保护OL免受谷氨酸、N-甲基-D-天冬氨酸、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸、喹啉酸和ROS的损伤，但对海藻酸、星形孢菌素、NO或犬尿烯酸无效。用促肾上腺皮质激素处理的MG的CM对这些分子均无保护作用，未用促肾上腺皮质激素处理的AS或MG的CM也无保护作用。虽然促肾上腺皮质激素对OL的几种毒性分子的保护作用涉及对OL的直接作用，但促肾上腺皮质激素也可刺激AS产生针对某些分子而非其他分子的保护介质。因此，促肾上腺皮质激素对OL保护作用的细胞机制很复杂，因毒性分子而异。
