Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease
Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease
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DOI：
10.1126/scitranslmed.aaf8732
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发表时间：
2016-10-26
影响因子：
17.1
通讯作者：
Loser, Karin
中科院分区：
文献类型：
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作者：
Mykicki, Nadine;Herrmann, Alexander M.;Loser, Karin
在炎症相关的进行性神经炎性疾病中，如多发性硬化症(MS)，含有T辅助细胞1(T(H)1)和T(H)17细胞的炎性浸润物会导致脱髓鞘和神经元变性。调节性T细胞(T-reg)控制自身反应性T细胞的激活和向中枢神经系统(CNS)的渗透。在MS和实验性自身免疫性脑脊髓炎(EAE)小鼠中，T-reg功能受损。我们发现最近批准的药物NLE(4)-D-Phe(7)-α-黑素细胞刺激素(NDP-MSH)可以诱导功能性T-reg，从而改善小鼠EAE的进展。NDP-MSH还通过恢复血脑屏障的完整性来防止免疫细胞渗透到中枢神经系统。NDP-MSH对EAE小鼠具有持久的神经保护作用，并能防止兴奋性死亡，并在体外重建小鼠和人神经元的动作电位放电。NDP-MSH的神经保护作用是通过黑素皮质素-1和孤儿核4受体介导的。NDP-MSH可能有益于治疗神经炎性疾病，如复发-缓解型MS和相关疾病。
In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (T(H)1) and T(H)17 cells cause demyelination and neuronal degeneration. Regulatory T cells (T-reg) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, T-reg function is impaired. We show that a recently approved drug, Nle(4)-D-Phe(7)-alpha-melanocyte-stimulating hormone (NDP-MSH), induced functional T-reg, resulting in amelioration of EAE progression in mice. NDP-MSH also prevented immune cell infiltration into the CNS by restoring the integrity of the blood-brain barrier. NDP-MSH exerted long-lasting neuroprotective effects in mice with EAE and prevented excitotoxic death and reestablished action potential firing in mouse and human neurons in vitro. Neuro-protection by NDP-MSH was mediated via signaling through the melanocortin-1 and orphan nuclear 4 receptors in mouse and human neurons. NDP-MSH may be of benefit in treating neuroinflammatory diseases such as relapsing-remitting MS and related disorders.