Department of Neurology, Wayne State University School of Medicine, Detroit, MI.
Department of Microbiology, Immunology and Biochemistry, Wayne State University School of Medicine, Detroit, MI.
J Neurosci Res. 2018 Mar;96(3):427-435. doi: 10.1002/jnr.24141. Epub 2017 Sep 6.
ACTH, a melanocortin peptide used to treat multiple sclerosis (MS) relapses, acts by stimulating adrenal corticosteroid (CS) production via melanocortin receptor 2 (MC2R), but it may also exert a therapeutic effect independent of CS by stimulating other melanocortin receptors (MCR) distributed in many tissues, including the brain. We reported that oligodendroglia (OL) and oligodendroglial precursor cells (OPC) express MC4R, and that ACTH 1-39 protects OL and OPC in vitro from cell death induced by mechanisms likely involved in white matter damage in MS. This study investigates expression of MC1R, MC2R, MC3R and MC5R in OL and MC4R in OPC using immunocytochemistry with MCR subtype specific antibodies. OL express surface MC1R, MC3R and MC5R, in addition to MC4R. To investigate whether these receptors are functional, we asked if signaling through MCR is involved in ACTH protection of cultured rat OL from apoptosis (staurosporine), or cell death induced by excitotoxicity (glutamate), reactive oxygen species (ROS), or an inflammatory mediator (quinolinic acid). Like ACTH 1-39, MCR subtype specific agonists for MC1R, MC3R, MC4R and MC5R all protected OL from these insults. Conversely, antagonists for MC3R and MC4R blocked ACTH protection of OL. We then investigated the role of MC4R, as a prototype MCR, in protection and proliferation of OPC; MC4R agonists protected OPC and increased their proliferation, while antagonists blocked these effects. Our results demonstrate that MCR on OL and OPC are functional and activate signaling pathways that protect against mechanisms involved in OL damage in MS, suggesting potential beneficial effects in neurologic diseases.
促肾上腺皮质激素（ACTH）是一种用于治疗多发性硬化症（MS）复发的黑素皮质素肽，通过刺激黑素皮质素受体 2（MC2R）来刺激肾上腺皮质激素（CS）的产生，但它也可能通过刺激分布在许多组织中的其他黑素皮质素受体（MCR）发挥治疗作用，包括大脑。我们报道了少突胶质细胞（OL）和少突胶质前体细胞（OPC）表达 MC4R，ACTH 1-39 可保护体外 OL 和 OPC 免受可能涉及 MS 白质损伤的机制诱导的细胞死亡。本研究使用 MCR 亚型特异性抗体的免疫细胞化学法研究 OL 中 MC1R、MC2R、MC3R 和 MC5R 的表达以及 OPC 中 MC4R 的表达。OL 表达表面 MC1R、MC3R 和 MC5R，以及 MC4R。为了研究这些受体是否具有功能，我们询问通过 MCR 信号转导是否参与 ACTH 保护培养的大鼠 OL 免受细胞凋亡（星形孢菌素）或兴奋性毒性（谷氨酸）、活性氧（ROS）或炎症介质（喹啉酸）诱导的细胞死亡。像 ACTH 1-39 一样，MCR 亚型特异性激动剂对 MC1R、MC3R、MC4R 和 MC5R 均能保护 OL 免受这些损伤。相反，MC3R 和 MC4R 的拮抗剂阻断了 ACTH 对 OL 的保护作用。然后，我们研究了 MC4R（作为原型 MCR）在保护和增殖 OPC 中的作用；MC4R 激动剂保护 OPC 并增加其增殖，而拮抗剂则阻断这些作用。我们的结果表明，OL 和 OPC 上的 MCR 具有功能，并激活信号通路，可防止 MS 中 OL 损伤相关的机制，这表明在神经疾病中具有潜在的有益作用。
