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Prospects for the pharmacotherapy of amyotrophic lateral sclerosis : old strategies and new paradigms for the third millennium. | LitMetric

AI Article Synopsis

  • Biomedical research on ALS has focused on reactive oxygen species (ROS) and glutamate excitotoxicity, leading to the development of riluzole, the only available drug, but it offers minimal therapeutic benefits and only modestly slows disease progression.
  • Current research efforts have not fully addressed neuronal loss and motor decline in ALS, highlighting the need for a deeper understanding of cell death processes and the molecular pathways involved.
  • New technologies that allow for the screening of protein changes in cells may be crucial in discovering more effective treatments for ALS by targeting the mechanisms of protein aggregation and oxidative stress.

Article Abstract

Biomedical researchers interested in amyotrophic lateral sclerosis (ALS) must invoke newly developing technologies if we are to discover pharmaceutical treatments that will help a significant population of patients with the disease. The focus of ALS research over the last 10 years has been on reactive oxygen species (ROS) and glutamate excitotoxicity, resulting in several clinical trials and the launch of the only drug currently available for the treatment of ALS, riluzole. Unfortunately, the therapeutic benefits have been minimal, at best, and the prognosis for patients with ALS has not improved beyond very modest retardation of the disease course. By emphasising ROS and glutamate excitotoxicity, current ALS research has only partially been able to attenuate the rate of motor decline and neuronal loss associated with this illness. Clues to additional therapeutic potentialities will come from an increased understanding of the mode of cell death (apoptotic or other) and the pathways leading to neuronal demise. If death is apoptotic, inhibiting caspases may be useful. The regulatory modifications for cell death at the molecular level remain to be determined and exploited to prevent neuronal loss, although novel pathways have been recently elucidated that impact on protein aggregation and processing. Oxidative stress, seen in both familial and sporadic forms of ALS, may be only one post-translational mechanism likely to affect specific proteins essential for the health and stability of motor neurons. Protein cross-linking by transglutaminase paralleling that may lead to defects in proteasome function may also be a significant mechanism. The latest capabilities to screen protein changes in specific cells represent the kinds of advances needed to combat ALS in the third millennium.

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Source
http://dx.doi.org/10.2165/00023210-200317100-00002DOI Listing

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