Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice
Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice
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DOI：
10.1016/j.brainres.2014.05.004
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发表时间：
2014-07-21
期刊：
影响因子：
2.9
通讯作者：
Quirico-Santos, Thereza
中科院分区：
文献类型：
--
作者：
Correa Leite, Paulo Emilio;Gandia, Luis;Quirico-Santos, Thereza
大量证据表明，α7 烟碱乙酰胆碱受体 (nAChR α7) 激活可减少炎症介质的产生。这项工作旨在验证内源性 nAChR α 7 激活对杜氏肌营养不良症 mdx 小鼠全面肌肉炎症调节的影响。我们使用 3 周龄高度肌坏死的 mdx 小鼠，以及腓肠肌中 60 μL 0.5% 布比卡因 (bp) 诱导肌肉损伤的 C57 nAChR α 7(+/+) 野生型和 nAChR α 7(-/-) 敲除小鼠。药物治疗包括腹腔注射选择性 nAChRa7 激动剂 PNU282987（0.3 mg/kg 和 1.0 mg/kg）和拮抗剂甲基利卡乌头碱（MLA 1.0 mg/kg），持续 7 天。使用 PNU282987 选择性激活 mdx 小鼠的 nAChR α 7 可降低乳酸脱氢酶（LDH，细胞坏死死亡标志物）的循环水平和血管周围炎症浸润面积，以及炎症介质 TNF α 和金属蛋白酶 MMP-9 活性的产生。相反，PNU282987 治疗增加了 MMP-2 活性，表明在患有 bp 诱导肌肉损伤的 mdx 小鼠和 WT α 7 小鼠中，MMP-2 活性与再生相关。 PNU282987 治疗对 α 7KO 没有影响，MLA 消除了 mdx 和 WT 中 nAChR α 7 激动剂诱导的抗炎作用。总之，nAChR α 7 激活可抑制肌肉炎症并通过增加肌肉再生来激活组织重塑。这些影响并不伴随纤维化和/或非功能性胶原蛋白的沉积。 nAChR α 7 激活可被视为减少炎症和激活肌肉再生机制的药理学策略的潜在靶点。 (C) 2014 Elsevier B.V. 保留所有权利。
Amount evidence indicates that alpha 7 nicotinic acetylcholine receptor (nAChR alpha 7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChR alpha 7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChR alpha 7(+/+) wild-type and nAChR alpha 7(-/-) knockout mice with muscular injury induced with 60 mu L 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRa7 agonist PNU282987 (0.3 mg/kg and 1.0 mg/kg) and the antagonist methyllycaconitine (MLA at 1.0 mg/kg) injected intraperitoneally for 7 days. Selective nAChR alpha 7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNF alpha and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WT alpha 7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on alpha 7KO, and MLA abolished the nAChR alpha 7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChR alpha 7 activation inhibits muscular inflammation and activates tissue remodeling by increasing muscular regeneration. These effects were not accompanied with fibrosis and/or deposition of non-functional collagen. The nAChR alpha 7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration. (C) 2014 Elsevier B.V. All rights reserved.