Neuronal Hyperexcitability and Free Radical Toxicity in Amyotrophic Lateral Sclerosis: Established and Future Targets

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disease with evidence of degeneration involving upper and lower motor neuron compartments of the nervous system. Presently, two drugs, riluzole and edaravone, have been established as being useful in slowing disease progression in ALS. Riluzole possesses anti-glutamatergic properties, while edaravone eliminates free radicals (FRs). Glutamate is the excitatory neurotransmitter in the brain and spinal cord and binds to several inotropic receptors. Excessive activation of these receptors generates FRs, inducing neurodegeneration via damage to intracellular organelles and upregulation of proinflammatory mediators. FRs bind to intracellular structures, leading to cellular impairment that contributes to neurodegeneration. As such, excitotoxicity and FR toxicities have been considered as key pathophysiological mechanisms that contribute to the cascade of degeneration that envelopes neurons in ALS. Recent advanced technologies, including neurophysiological, imaging, pathological and biochemical techniques, have concurrently identified evidence of increased excitability in ALS. This review focuses on the relationship between FRs and excitotoxicity in motor neuronal degeneration in ALS and introduces concepts linked to increased excitability across both compartments of the human nervous system. Within this cellular framework, future strategies to promote therapeutic development in ALS, from the perspective of neuronal excitability and function, will be critically appraised.

Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice

“…Much evidence suggests a pivotal role for NMDAR-mediated excitotoxicity in the pathogenesis of ALS (2,3); for this reason we investigated the in vivo effect of the NMDA receptor antagonist REL-1017 on ALS onset and progression in the G93A SOD1 mouse.…”

“…Numerous lines of evidence indicate the involvement of excitotoxicity in the pathogenesis of ALS (2), suggesting that reducing excessive Ca 2+ influx via NMDA receptors could postpone or prevent motor neuronal death. Excitotoxicity can be induced by excessive synaptic glutamate, due to either increased release of glutamate or impaired glutamate uptake; excitotoxicity can also be induced by endogenous or exhogenous molecules acting as competitive agonists at the glutamate site or molecules acting as positive allosteric modulators of the NMDARs.…”

Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis

“…Our findings provide new evidence that supports the concepts that aberrations in cellular structure and function contribute to ALS pathology, via specific effects in individual lipidomic pathways, potentially guiding more precise therapeutic approaches. 61 …”

New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases

“…Finally, hyperexcitability is a decisive characteristic of ALS, and it was detected before early clinical symptoms, with a strengthening which causes disruption in energy metabolism, mitochondrial disfunctions, and increased OS [ 155 , 156 , 157 ]. This altered neuronal excitability and the consequent manifestation of OS were associated with defects in ion channels, including sodium, potassium, calcium, and chloride ones, of neuronal and non-neuronal cells [ 158 ]. In fact, while most ALS patients do not manifest deleterious mutations in ion channel-associated genes, many studies reported alterations in channels in both mutated and non-mutated ALS subjects and animal models [ 158 , 159 ].…”

“…This altered neuronal excitability and the consequent manifestation of OS were associated with defects in ion channels, including sodium, potassium, calcium, and chloride ones, of neuronal and non-neuronal cells [ 158 ]. In fact, while most ALS patients do not manifest deleterious mutations in ion channel-associated genes, many studies reported alterations in channels in both mutated and non-mutated ALS subjects and animal models [ 158 , 159 ]. Already in 2006, Kaiser and co-authors demonstrated a reduction in potassium channels in SOD1 G93A mice leading inevitably to MN death.…”