Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice.
Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 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 nAChRα7(+/+) wild-type and nAChRα7(-/-) knockout mice with muscular injury induced with 60µL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3mg/kg and 1.0mg/kg) and the antagonist methyllycaconitine (MLA at 1.0mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 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 TNFα 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 WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 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 nAChRα7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration.
Department of Cellular and Molecular Biology, Fluminense Federal University, Rio de Janeiro, Brazil. Electronic address: leitepec@gmail.com.
Paulo Emílio Correa
PE
Leite
Instituto Teófilo Hernando, Department of Pharmacology and Therapeutics, Autonomous University of Madrid, Madrid, Spain. Electronic address: luis.gandia@uam.es.
Luís
L
Gandía
Instituto Teófilo Hernando, Department of Pharmacology and Therapeutics, Autonomous University of Madrid, Madrid, Spain. Electronic address: ricardo.pascual@uam.es.
Ricardo
R
de Pascual
Instituto Teófilo Hernando, Department of Pharmacology and Therapeutics, Autonomous University of Madrid, Madrid, Spain. Electronic address: carmen.perezd@uam.es.
Carmen
C
Nanclares
Instituto Teófilo Hernando, Department of Pharmacology and Therapeutics, Autonomous University of Madrid, Madrid, Spain. Electronic address: ines.colmena@uam.es.
Inés
I
Colmena
Instituto Teófilo Hernando, Department of Pharmacology and Therapeutics, Autonomous University of Madrid, Madrid, Spain; Department of Pharmacy Administration, Fluminense Federal University, Rio de Janeiro, Brazil. Electronic address: wsantos@id.uff.br.
Wilson C
WC
Santos
Department of Immunobiology, Fluminense Federal University, Rio de Janeiro, Brazil. Electronic address: lagrota-candido@vm.uff.br.
Jussara
J
Lagrota-Candido
Department of Cellular and Molecular Biology, Fluminense Federal University, Rio de Janeiro, Brazil. Electronic address: tquirico@vm.uff.br.
Thereza
T
Quirico-Santos
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002045:Bupivacaine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne; D009336:Necrosis / Q000188:drug therapy / Q000503:physiopathology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; C498513:PNU-282987; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D000157:Aconitine; D002045:Bupivacaine
Acetylcholine receptor; Cholinergic anti-inflammatory pathway; Inflammation; Mdx mice; Muscular dystrophy; Skeletal muscle