ACTH protects mature oligodendroglia from excitotoxic and inflammation-related damage in vitro
ACTH protects mature oligodendroglia from excitotoxic and inflammation-related damage in vitro
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DOI：
10.1002/glia.22504
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发表时间：
2013-08-01
期刊：
影响因子：
6.2
通讯作者：
Lisak, Robert P.
中科院分区：
文献类型：
--
作者：
Benjamins, Joyce A.;Nedelkoska, Liljana;Lisak, Robert P.
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，还刺激CS产生。外源性ACTH 1-39用于治疗MS复发，推测是通过刺激内源性CS产生。然而，与CS不同的是，ACTH结合于在中枢神经系统（CNS）以及炎性细胞中发现的黑皮质素受体。由于神经胶质细胞参与MS和其他神经退行性疾病，少突胶质细胞（OL）比其他神经胶质细胞对损伤更敏感，我们的特点是在没有CS的混杂作用的情况下，在体外对OL的ACTH的保护作用。将含有OL、星形胶质细胞（AS）和小胶质细胞（MG）的大鼠脑培养物与潜在的细胞毒性剂一起孵育1天，并与ACTH 1-39一起预孵育或不预孵育。细胞毒性药物杀死55-70%的成熟OL，但在所用浓度下几乎不引起AS或MG死亡。ACTH保护OL免于由星形孢菌素、AMPA、NMDA、红藻氨酸盐、喹啉酸或活性氧引起的死亡，但不保护免受犬尿烯酸或一氧化氮的影响。ACTH的保护作用是剂量依赖性的，并且在200 nM ACTH下使由不同药剂诱导的OL死亡减少30-60%。我们首次发现，除了MG和AS外，黑素皮质素4受体在OL上也有表达。总之，ACTH 1-39在体外保护OL免受几种兴奋毒性和炎症相关的损伤。ACTH可能激活OL或AS或MG上的黑皮质素受体，以防止OL死亡。GLIA 2013;61：1206-1217
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. GLIA 2013;61:1206-1217