Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Glia. 2013 Aug;61(8):1206-17. doi: 10.1002/glia.22504. Epub 2013 Jul 5.
Corticosteroids (CS) are widely employed to treat relapses in multiple sclerosis (MS). Endogenous ACTH is a 39-amino acid peptide that, among other functions, stimulates CS production. Exogenous ACTH 1-39 is used to treat MS relapses, presumably by stimulating endogenous CS production. However, unlike CS, ACTH binds to melanocortin receptors, found in the central nervous system (CNS) as well as on inflammatory cells. Since glia are implicated in MS and other neurodegenerative diseases, and oligodendroglia (OL) are more sensitive to injury than other glia, we characterized the protective effects of ACTH on OL in vitro without the confounding effects of CS. Rat brain cultures containing OL, astrocytes (AS), and microglia (MG) were incubated for 1 day with potentially cytotoxic agents with or without preincubation with ACTH 1-39. The cytotoxic agents killed 55-70% of mature OL, but caused little or no death of AS or MG at the concentrations used. ACTH protected OL from death induced by staurosporine, AMPA, NMDA, kainate, quinolinic acid, or reactive oxygen species, but did not protect against kynurenic acid or nitric oxide. The protective effects of ACTH were dose dependent, and decreased OL death induced by the different agents by 30-60% at 200 nM ACTH. We show for the first time that melanocortin 4 receptor is expressed on OL in addition to MG and AS. In summary, ACTH 1-39 protects OL in vitro from several excitotoxic and inflammation-related insults. ACTH may be activating melanocortin receptors on OL or alternately on AS or MG to prevent OL death.
皮质类固醇（CS）被广泛用于治疗多发性硬化症（MS）的复发。内源性 ACTH 是一种 39 个氨基酸的肽，除了其他功能外，还能刺激 CS 的产生。外源性 ACTH 1-39 用于治疗 MS 复发，可能是通过刺激内源性 CS 的产生。然而，与 CS 不同，ACTH 与中枢神经系统（CNS）以及炎症细胞上的黑皮质素受体结合。由于神经胶质细胞与 MS 和其他神经退行性疾病有关，而少突胶质细胞比其他神经胶质细胞更容易受到损伤，因此我们在没有 CS 干扰作用的情况下，在体外对 ACTH 对少突胶质细胞的保护作用进行了特征描述。含有少突胶质细胞、星形胶质细胞（AS）和小胶质细胞（MG）的大鼠脑培养物在含有或不含有 ACTH 1-39 的潜在细胞毒性药物中孵育 1 天。细胞毒性药物杀死了 55-70%的成熟 OL，但在使用的浓度下，AS 或 MG 的死亡很少或没有。ACTH 可保护 OL 免受星形孢菌素、AMPA、NMDA、海人藻酸、喹啉酸或活性氧诱导的死亡，但不能防止犬尿氨酸或一氧化氮。ACTH 的保护作用呈剂量依赖性，在 200 nM ACTH 时，可将不同药物诱导的 OL 死亡减少 30-60%。我们首次证明，黑皮质素 4 受体除了在 MG 和 AS 上表达外，还在 OL 上表达。总之，ACTH 1-39 可保护体外的 OL 免受多种兴奋性毒性和炎症相关损伤。ACTH 可能通过激活 OL 上的黑皮质素受体，或通过激活 AS 或 MG 上的黑皮质素受体，来防止 OL 死亡。
