Neuroprotective agents target molecular mechanisms of disease in ALS

• Published in: Drug discovery today 2015-01, Vol.20 (1), p.65-75
• Main Authors: Zhu, Yongjin, Fotinos, Anastasios, Mao, Lilly L.J., Atassi, Nazem, Zhou, Edward W., Ahmad, Sarfraz, Guan, Yingjun, Berry, James D., Cudkowicz, Merit E., Wang, Xin
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - drug therapy; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Muscular Atrophy - drug therapy; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Structure-Activity Relationship; Weight Loss - drug effects
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2014.08.016

•Comparing agents used in ALS animal models by onset, survival and muscle damage.•Agents are organized by individual mechanisms and effects summarized.•Analysis of structure–activity relationship of agents that reduce bodyweight loss. Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weight loss and respiratory failure. Evidence suggests that inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and proteasomal dysfunction are all responsible for ALS pathogenesis. We review neuroprotective agents with the ability to reduce ALS-related bodyweight loss, summarize the various therapies tested on animal models targeting the proposed molecular mechanisms, compare their effects on bodyweight loss, muscle damage, disease onset, duration and survival, and analyze their structure–activity relationships, with the overall goal of creating a screening strategy for further clinical application.