β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS)

NEUROBIOLOGY OF DISEASE

卷:85

Review

Bartus, Raymond T.¹  Betourne, Alexandre²  Basile, Anthony³  Peterson, Bethany L.²  Glass, Jonathan^4,5  Boulis, Nicholas M.⁶ 

[1] RTBioconsultants Inc, San Diego, CA 92130 USA

[2] Above & Beyond LLC, Atlanta, GA USA

[3] Independent Consultant, Carlsbad, CA USA

[4] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[5] Emory Univ, Sch Med, Emory ALS Ctr, Atlanta, GA USA

[6] Emory Univ, Sch Med, Dept Surg, Atlanta, GA 30322 USA

关键词: beta(2)-Adrenoceptor agonists;    Repurposing drugs;    ALS;    Neuroprotection;    Neurorestoration;    Anabolic muscle effects;    Neuromuscular junction;    Motor neuron degeneration;    Neuromuscular disease;   

DOI  :  10.1016/j.nbd.2015.10.006

来源: Elsevier

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved beta(2)-adrenoceptor agonists may effectively treat the symptoms and possibly slow the progression of ALS. Although beta(2)-agonists are primarily used to treat asthma, pharmacologic data from animal models of neuromuscular diseases suggest that these agents may have pharmacologic effects of benefit in treating ALS. These include inhibiting protein degradation, stimulating protein synthesis, inducing neurotrophic factor synthesis and release, positively modulating microglial and systemic immune function, maintaining the structural and functional integrity of motor endplates, and improving energy metabolism. Moreover, stimulation of beta(2)-adrenoceptors can activate a range of downstream signaling events in many different cell types that could account for the diverse array of effects of these agents. The evidence supporting the possible therapeutic benefits of (beta(2)-agonists is briefly reviewed, followed by a more detailed review of clinical trials testing the efficacy of beta-agonists in a variety of human neuromuscular maladies. The weight of evidence of the potential benefits from treating these diseases supports the hypothesis that beta(2)-agonists may be efficacious in ALS. Finally, ways to monitor and manage the side effects that may arise with chronic administration of beta 2-agonists are evaluated. In sum, effective, safe and orally-active beta(2)-agonists may provide a novel and convenient means to reduce the symptoms of ALS and possibly delay disease progression, affording a unique opportunity to repurpose these approved drugs for treating ALS, and rapidly transforming the management of this serious, unmet medical need. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.

【 授权许可】

Free