期刊
BRAIN RESEARCH
卷 1573, 期 -, 页码 27-36出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2014.05.004
关键词
Skeletal muscle; Mdx mice; Muscular dystrophy; Inflammation; Acetylcholine receptor; Cholinergic anti-inflammatory pathway
资金
- CAPES-DGU program (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)
- FAPERJ (Fundacao de Amparo a Pesquisa do Rio de Janeiro)
- MEC (Ministerio de Economia y Competitividad, Spain) [SAF-2010-18837]
- CEAL-Santander
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.
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