Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle

Abstract

Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function and weakness leading to paralysis. This pathology is the result of a complex cascade of events that involves a crosstalk among motor neurons, glia, and muscles, and evolves through the action of converging toxic mechanisms. In fact, mitochondrial dysfunction, which leads to oxidative stress, is one of the mechanisms causing cell death. It is a common denominator for the two existing forms of the disease: sporadic and familial. Other factors include excitotoxicity, inflammation, and protein aggregation. Currently, there are limited cures. The only approved drug for therapy is riluzole, that modestly prolongs survival, with edaravone now waiting for new clinical trial aimed to clarify its efficacy. Thus, there is a need of effective treatments to reverse the damage in this devastating pathology. Many drugs have been already tested in clinical trials and are currently under investigation. This review summarizes the already tested drugs aimed at restoring muscle-nerve cross-talk and on new treatment options targeting this tissue.

“Calcium bombs” as harbingers of synaptic pathology and their mitigation by magnesium at murine neuromuscular junctions

“…However, there is no ubiquitous association with any specific risk factor or molecular mechanism that forms a basis for a unifying theory of ALS/FTD ( Keon et al, 2021 ). Excitotoxicity has been hypothesized to trigger several forms of neurodegenerative disease, and it has long been considered a potential explanation for ALS, as well as providing a rationale for its mitigation by riluzole or edavorone, presently the only fully licensed treatments for ALS ( Cheah et al, 2010 ; Brooks et al, 2022 ; Sever et al, 2022 ; Tarantino et al, 2022 ). However, the potential associations between activity or excitotoxicity with ALS or FTD remain controversial ( Chiò et al, 2005 ; Huisman et al, 2013 ; Gallo et al, 2016 ; Starr and Sattler, 2018 ).…”

Amyotrophic Lateral Sclerosis and Serum Lipid Level Association: A Systematic Review and Meta-Analytic Study

“…Most of the pharmacological treatments used in ALS are symptomatic treatments: spasticity (muscle relaxants or cannabinoids [84]), sialorrhoea (hypersalivation) (anticholinergic drugs), pain (tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, opioids, and cannabis), respiratory insufficiency (noninvasive ventilation), and others [5]. In addition, great interest has been placed in research on drugs that act on ion channels and on skeletal muscle [85,86]. These authors have even established the possible relationship between ALS, muscle atrophy, and the taking of statins (atorvastatin) (drug used to lower serum cholesterol levels) [87].…”

New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases

“…Already in 2006, Kaiser and co-authors demonstrated a reduction in potassium channels in SOD1 G93A mice leading inevitably to MN death. More recently, alterations in chloride channels were associated with muscle channelopathies, atrophy, and OS [ 160 , 161 ] and the decreased expression of calcium channels in the spinal MNs of SOD1 G93A mice was correlated with excess mitochondrial calcium and the production of ROS [ 162 , 163 ].…”