Journal
AGEING RESEARCH REVIEWS
Volume 83, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.arr.2022.101790
Keywords
Amyotrophic Lateral Sclerosis; Mitochondria; Oxidative stress; Ferroptosis; Hypoxia-inducible factor; Nuclear Factor kappa B
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Amyotrophic lateral sclerosis (ALS) is a progressive disease that leads to paralysis and death due to respiratory failure. Current ALS drugs only provide mild relief to patients. Recent advances in understanding ALS biology have identified potential targets for drug development, including mitochondria and oxidative stress, iron metabolism and ferroptosis, and regulators of hypoxia and inflammation. This review focuses on discussing the latest advances in ALS drug development and proposes the rational design of multi-target ligands as a potential effective therapy for ALS.
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by respiratory failure 3-5 years after diagnosis. Edaravone and Riluzole, the only drugs currently approved for ALS treatment, only provide mild symptomatic relief to patients. Extraordinary progress in understanding the biology of ALS provided new grounds for drug discovery. Over the last two decades, mitochondria and oxidative stress (OS), iron metabolism and ferroptosis, and the major reg-ulators of hypoxia and inflammation - HIF and NF-kappa B - emerged as promising targets for ALS therapeutic intervention. In this review, we focused our attention on these targets to outline and discuss current advances in ALS drug development. Based on the challenges and the roadblocks, we believe that the rational design of multi -target ligands able to modulate the complex network of events behind the disease can provide effective therapies in a foreseeable future.
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