Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

Palma Eleonora; Reyes-Ruiz Jorge Mauricio; Lopergolo DiegoRoseti CristinaBertollini CristinaRuffolo GabrieleCifelli PierangeloOnesti EmanuelaLimatola CristinaMiledi RicardoInghilleri Maurizio

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Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

机译：Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons that leads to progressive paralysis of skeletal muscle. Studies of ALS have revealed defects in expression of acetylcholine receptors (AChRs) in skeletal muscle that occur even in the absence of motor neuron anomalies. The endocannabinoid palmitoylethanolamide (PEA) modified the clinical conditions in one ALS patient, improving muscle force and respiratory efficacy. By microtransplanting muscle membranes from selected ALS patients into Xenopus oocytes, we show that PEA reduces the desensitization of acetylcholine-evoked currents after repetitive neurotransmitter application (i.e., rundown). The same effect was observed using muscle samples from denervated (non-ALS) control patients. The expression of human recombinant alpha 1 beta 1 gamma delta (gamma-AChRs) and alpha 1 beta 1 epsilon delta AChRs (epsilon-AChRs) in Xenopus oocytes revealed that PEA selectively affected the rundown of ACh currents in epsilon-AChRs. A clear up-regulation of the alpha 1 subunit in muscle from ALS patients compared with that from non-ALS patients was found by quantitative PCR, but no differential expression was found for other subunits. Clinically, ALS patients treated with PEA showed a lower decrease in their forced vital capacity (FVC) over time as compared with untreated ALS patients, suggesting that PEA can enhance pulmonary function in ALS. In the present work, data were collected from a cohort of 76 ALS patients and 17 denervated patients. Our results strengthen the evidence for the role of skeletal muscle in ALS pathogenesis and pave the way for the development of new drugs to hamper the clinical effects of the disease.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2016年第11期|3060-3065|共6页
作者
Palma Eleonora; Reyes-Ruiz Jorge Mauricio; Lopergolo DiegoRoseti CristinaBertollini CristinaRuffolo GabrieleCifelli PierangeloOnesti EmanuelaLimatola CristinaMiledi RicardoInghilleri Maurizio;
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作者单位

Univ Roma La Sapienza, Ist Pasteur Fdn Cenci Bolognetti, Dept Physiol & Pharmacol, I-00185 Rome, Italy;

Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA;

Univ Roma La Sapienza, Dept Neurol & Psychiat, I-00185 Rome, ItalyIst Ricovero & Cura Carattere Sci San Raffaele Pi, I-00166 Rome, Italy;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
ALS; muscle AChR; Xenopus oocytes; microtransplantation; qPCR;

Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

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