Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is the most severe form of motor neuron degeneration. This study aims to: (1) compare genetic and non-genetic contributors to ALS development, (2) evaluate the pharmacological mechanisms of riluzole and its therapeutic potential across multiple conditions, and (3) explore treatment combinations for managing symptoms throughout ALS progression. The analysis was conducted using data from established electronic medical databases. The most frequently implicated genetic mutations in ALS include SOD1, SETX, FUS, VEGF, VAPB, ANG, TARDBP, FIG4, OPTN, ATXN2, VCP, UBQLN2, SIGMAR1, CHMP2B, PFN1, ERBB4, HNRNPA1, C9orf72, dynactin 1, H46R, and A4V. Additional risk factors include oxidative stress, glutamate-induced excitotoxicity, autoimmune responses, protein misfolding and aggregation, inflammation, and viral infections. Riluzole’s therapeutic actions are attributed to several mechanisms: (1) inhibition of repetitive neuronal firing, (2) blockade of persistent sodium currents in motor neurons, (3) enhancement of calcium-activated potassium currents, (4) reduction of presynaptic neurotransmitter release, and (5) attenuation of postsynaptic receptor responses. Combining riluzole with antioxidants such as vitamins E and C, coenzyme Q10, creatine, and selenium may enhance therapeutic efficacy in ALS. Symptomatic treatments include nonsteroidal anti-inflammatory drugs, opioids for pain relief, and agents like Baclofen and Dantrolene to manage spasticity. Memantine, Nimesulide, and Gabapentin show promise for further research. Due to its diverse mechanisms, riluzole is also being investigated for use in Parkinson’s disease, Huntington’s disease, Machado-Joseph disease, multiple sclerosis, spinal muscular atrophy, and various neuropsychiatric conditions, including anxiety, autism, depression, and schizophrenia.
Neurodegenerative disorders such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), Lewy body dementia, multiple sclerosis, and mitochondrial conditions like Friedreich’s ataxia and Leber’s hereditary optic neuropathy are marked by progressive deterioration of the nervous system. This deterioration typically involves the structural and functional decline or death of neurons [1, 2]. The underlying pathogenic mechanisms contributing to this degeneration include mitochondrial dysfunction [3], oxidative stress [4], protein aggregation [5], membrane damage, and apoptosis [1].
In Alzheimer’s disease, neurofibrillary tangles—comprising beta-amyloid plaques [6, 7], alpha-synuclein aggregates, and hyperphosphorylated tau protein—are a hallmark feature [6]. Similarly, alpha-synuclein accumulation is characteristic of several related disorders, including Parkinson’s disease, Lewy body dementia, and multiple system atrophy [5, 8].
Various therapeutic approaches have been employed to manage Alzheimer’s disease [9], with acetylcholinesterase inhibitors such as galantamine playing a significant role due to their dual cognitive and antioxidant effects [10, 11]. Other potential treatments under investigation include phenacyl derivatives of 9-aminoacridine [12, 13] and newly synthesized 1,3-di-4-piperidylpropane derivatives, which show promising acetylcholinesterase-inhibitory activity [14].
Primary lateral sclerosis results from degeneration of upper motor neurons, whereas progressive muscular atrophy is associated with degeneration of lower motor neurons [15, 16]. ALS, also known as Charcot disease, is the most severe motor neuron disorder, characterized by degeneration of both upper and lower motor neurons. This leads to muscle weakness, atrophy, and eventual paralysis affecting the limbs, trunk, and bulbar regions. Patients often experience dysarthria, dysphagia, cramps, stiffness, and progressive loss of motor functions. In advanced stages, sensory impairments—such as diminished sight, hearing, and tactile perception—may also occur.
This study aims to: (1) compare genetic and non-genetic contributors to ALS development, (2) evaluate the pharmacological mechanisms of riluzole and its therapeutic potential across multiple conditions, and (3) explore treatment combinations for managing symptoms throughout ALS progression.
ALS is more common in males and occurs across all racial and ethnic groups, with an estimated incidence of 2 per 100,000 per year in Europe [17], 4 per 100,000 among Caucasians [18], and 3 per 100,000 in Filipino populations. Cognitive deficits are reported in 20% to 50% of ALS cases, with dementia occurring in approximately 5% to 15% of patients [19]. Key epidemiological and clinical data related to ALS are summarized in Table 1.
Table 1. Essential data for ALS [17, 19]
1824 | The descriptions of the disease by Charles Bell |
1850 | The discovery of shriveled nerve fibers by the English scientist Augustus Waller |
1869 | Firstly, a description of the connection between the symptoms and the neurological problems by Jean-Martin Charcot [19] |
1874 | Introduction of the term ALS from Jean-Martin Charcot [19] |
1941 | The death from ALS of baseball player Lou Gehrig [19] |
1950 | |
1993 | The discovery of mutations of the SOD1 gene on chromosome 21 for familial ALS (FALS) [19] |
1996 | The first FDA-approved ALS treatment is riluzole [20]. |
1998 | The creation of criteria to serve as the industry standard for categorizing ALS in clinical research [18] |
2011 | Frontotemporal dementia and ALS have both been linked to noncoding repeat expansions in the C9ORF72 gene [21]. |
ALS typically begins around age 60 years, though in familial cases, onset may occur as early as age 50 [17]. Early manifestations of lower motor neuron degeneration include muscle cramps, progressive weakness, muscle atrophy, hyporeflexia, and hypotonia. Less typical initial symptoms include pain and cognitive decline, such as dementia [22]. Clinical presentation varies depending on the site of neuronal degeneration, with patients exhibiting either bulbar symptoms—such as difficulties in speech, chewing, and swallowing—or limb-related symptoms including fatigue and limb weakness.
Signs of upper motor neuron involvement include muscle weakness, slowed movements, stiffness, pathological reflexes, hyperreflexia, and a positive Babinski reflex. Approximately 45% of ALS patients exhibit pseudobulbar affect due to upper motor neuron degeneration, resulting in involuntary emotional expressions such as inappropriate laughing or crying. Disease progression is more rapid in cases involving frontotemporal dementia, respiratory impairment, or bulbar involvement.
The most common ALS-associated mutation in North America involves the SOD1 gene, typically leading to a rapid clinical course. Conversely, patients under 40 years of age who present with symptoms confined to the upper motor neurons and who are moderately overweight tend to experience slower disease progression [23]. In Scandinavian populations, the D90A SOD1 mutation is the most prevalent; it is associated with a slower disease course and an average survival of up to 11 years. This Asp90Ala mutation in the CuZn-superoxide dismutase gene is linked to an autosomal recessive form of ALS [24].
As the disease advances, patients progressively lose the ability to move, speak (dysarthria), swallow (dysphagia), and control tongue motion. In the late stages, oculomotor neuron degeneration (ophthalmoplegia) can impair voluntary saccadic eye movements, reducing both speed and accuracy [25]. Respiratory decline is a major concern in advanced ALS due to weakening of the intercostal muscles that support breathing. Aspiration pneumonia and respiratory failure, resulting from diaphragmatic and thoracic muscle paralysis, are leading causes of death. The median survival time post-diagnosis is approximately 39 months, with a typical range of three to five years. Only about 10% of patients survive beyond ten years, and fewer than 4% surpass this threshold. The extended survival of physicist Stephen Hawking—over 50 years—is considered a rare outlier. Notably, cachexia in ALS patients often develops despite minimal muscle mass loss [26].
Frontotemporal dementia occurs in roughly 5% of ALS cases. While 90%–95% of ALS cases are sporadic, the remaining 5%–10% are familial, inherited in an autosomal dominant or recessive manner [17]. Mutations in over 40 genes have been implicated in ALS. Among familial cases, mutations in the SOD1 gene account for 10%–20%, while they represent about 7% of sporadic cases [24]. Other key genetic contributors include TARDBP and FUS/TLS, responsible for approximately 8% of familial and 1% of sporadic cases [27].
Astrocytes are also implicated in motor neuron toxicity. In 1993, a mutation on chromosome 21 in astrocytes—coding for the antioxidant enzyme CuZn-superoxide dismutase (SOD1)—was identified as the cause of approximately 20% of familial ALS cases [28, 29]. This enzyme plays a crucial role in mitigating oxidative stress by neutralizing mitochondrial superoxide radicals. Dysfunction or deficiency in SOD1 leads to oxidative damage to DNA and cellular proteins due to superoxide accumulation [24]. More than 110 SOD1 mutations have been identified; among these, H46R is associated with a slower disease course, while A4V is associated with rapid progression.
The most frequent cause of sporadic ALS involves hexanucleotide repeat expansions in the C9orf72 gene on chromosome 9 and FUS protein aggregation [27]. The C9orf72 mutation, discovered in 2011, accounts for a significant portion of ALS cases with coexisting frontotemporal dementia (ALS-FTD), particularly in 6% of European and Filipino populations [21]. A summary of common ALS subtypes and their associated genetic mutations is presented in Table 2.
Table 2. Forms of ALS and their associated mutations
1 | ALS1 | SOD1 [24] | 10 | ALS13 | |
2 | ALS2 | ALS2 | 11 | ALS14 [29] | L106F |
3 | ALS4 | SETX | 12 | ALS15 [30] | |
4 | ALS6 | FUS [27] | 13 | ALS16 [31] | |
5 | ALS8 | VAPB | 14 | ALS17 | |
6 | ALS9 | ANG | 15 | ALS18 [32] | |
7 | ALS10 | TARDBP [27] | 16 | ALS19 [33] | |
8 | ALS11 | FIG4 | 17 | ALS20 [34] | |
9 | ALS12 | OPTN | 18 | ALS-FTD [21] |
Mutations in the VEGF gene, located on chromosome 6p21.3, particularly in isoforms such as VEGF121, VEGF145, VEGF165, VEGF183, VEGF189, and VEGF206, have been associated with impaired vascular perfusion [35]. This reduction in blood flow contributes to two major pathological consequences:
The onset of hypoxia leads to the production of mitochondrial reactive oxygen and nitrogen species (ROS and RNS) [36].
A decline in glucose availability, thereby limiting cellular energy production.
The functional consequences of various gene mutations implicated in ALS are outlined in Table 3.
Table 3. Effects of gene mutations in ALS
Gene mutation | Effect |
Superoxide dismutase 1 (SOD1) [24] | Familial ALS (FALS) |
CHMP2B (charged multivesicular protein 2B) [37] | Involved in cellular transport |
VEGF at chromosome 6p21.3 [35] | Deficiency of oxygen [36] |
VAPB - vesicle-associated membrane protein B [38] | Providing protein response to the endoplasmic reticulum |
dynactin 1 [39] | Involved in the axonal transport of nerve cells |
SETX-senataxin | Role in DNA repair in the brain and muscle |
Angiogenin [40, 41] | Role in neovascularisation |
Among the numerous factors contributing to the multifactorial etiology of ALS, several additional risk elements have been identified [19]. These include:
Exposure to toxic metals such as lead, cadmium, and arsenic, along with organophosphates, electromagnetic fields, smoking, and consumption of diets high in glutamate and fat. These factors promote systemic oxidative stress by stimulating the generation of free radicals [42].
Glutamate excitotoxicity results from excessive release of glutamic acid from presynaptic terminals in the central nervous system (CNS).
Deficiency of trophic growth factors.
Accumulation of insoluble intracellular protein aggregates in astrocytes and motor neurons [43].
Autoimmune-mediated neuronal damage.
Inherent susceptibility of motor neurons to degeneration.
Protein misfolding and aggregation, inflammatory responses, and cytoskeletal abnormalities.
Viral infections.
Reactive oxygen species (ROS) are natural byproducts of mitochondrial respiration, and their levels are regulated by mitochondrial antioxidant systems such as manganese superoxide dismutase and glutathione peroxidase. Oxidative stress—defined by an imbalance between free radical production and antioxidant defense—is a central pathogenic mechanism in neurodegeneration. It contributes to cellular damage by oxidizing proteins, nucleic acids, and lipids [4, 5].
The cellular antioxidant defense system includes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase. When free radical levels exceed the buffering capacity of these systems, oxidative stress ensues, forming the basis for a wide range of chronic conditions [44], such as autism spectrum disorders [45], atherosclerosis, type 1 and type 2 diabetes, Down syndrome [46], hypertension, schizophrenia, vascular disorders, age-related macular degeneration [47], psoriatic arthritis [48], and neurodegenerative disorders [49] including Alzheimer’s disease [50, 51], Parkinson’s disease, Huntington’s disease, and ALS (Lou Gehrig’s disease) [19].
Due to its high oxygen demand, abundance of polyunsaturated fatty acids, and limited endogenous antioxidant defenses, the brain is especially vulnerable to oxidative damage. In ALS and Alzheimer’s disease, oxidative stress arises from an imbalance between heightened production of reactive oxygen and nitrogen species (ROS/RNS) and a decline in antioxidant capacity [52]. These reactive species not only impair the cellular components of motor neurons but also affect surrounding glial cells, ultimately contributing to the degeneration seen in sporadic ALS [52–54].
In ALS patients, elevated oxidative stress biomarkers have been detected in cerebrospinal fluid, plasma, and urine. Notable indicators include 8-hydroxy-2'-deoxyguanosine (8-oxodG), a marker of DNA damage [53], and 4-hydroxy-2,3-nonenal (4-HNE), a lipid peroxidation product that is increased in serum [52].
Riluzole, a neuroprotective agent, remains the only drug approved by the U.S. Food and Drug Administration (FDA) since 1995 for ALS treatment [54]. It has demonstrated efficacy in slowing symptom progression [55], extending survival [56, 57], and increasing both short- and long-term survival durations [58–60]. Long-term use of riluzole has shown particularly favorable outcomes in sporadic forms of the disease [61].
A major pathogenic factor in ALS is glutamate-mediated excitotoxicity, in which excessive glutamate release and subsequent overstimulation of postsynaptic receptors increase sodium influx through glutamate receptor-gated ion channels. This process promotes oxidative stress, ultimately resulting in motor neuron necrosis and apoptosis [19, 62].
Riluzole exerts its neuroprotective effects through multiple mechanisms, including the activation of G-protein-coupled pathways that inhibit presynaptic glutamate release. It also reduces postsynaptic glutamate excitotoxicity by noncompetitively blocking N-methyl-D-aspartate (NMDA) receptors, thereby mitigating motor neuron overstimulation. Additionally, riluzole decreases cerebral glucose metabolism, thereby enhancing resistance to hypoxia by inactivating voltage-dependent sodium channels on glutamatergic terminals [63].
At lower concentrations (< 1–10 µM), riluzole demonstrates several beneficial actions relevant to ALS progression [63], such as:
Reduction of repetitive neuronal firing frequency [64].
Suppression of the persistent sodium current in motor neurons, a factor linked to neuronal hyperexcitability.
Enhancement of calcium-dependent potassium currents.
Decreased presynaptic neurotransmitter release.
Attenuation of postsynaptic neurotransmitter receptor responses.
The drug also reduces neurotransmitter release through:
Inhibition of voltage-gated presynaptic calcium channels (at 10–40 µM), resulting in reduced calcium influx.
Diminution of fast and persistent sodium currents, which lowers presynaptic excitability [63].
Enhancement of calcium-dependent potassium currents is observed at concentrations between 2–20 µM, while higher doses (20–100 µM) inhibit voltage-gated potassium currents [63]. The recommended therapeutic dosage of riluzole is 50 mg twice daily, available as an oral tablet [65] and an oral suspension containing 5 mg/mL [66].
Beyond ALS, Riluzole has shown therapeutic efficacy in other neurodegenerative diseases marked by neuronal loss and motor dysfunction, including Parkinson’s disease, Huntington’s disease, atypical Parkinsonism, and hereditary ataxias [67-70]. It has been effective in early Parkinson’s disease, reducing dyskinesia and prolonging motor control [71, 72]. In Huntington’s disease, riluzole counters brain glucose hypometabolism and stimulates neurotrophin production [73]. It is also used in the treatment of cerebellar ataxias, including hereditary cerebellar ataxia and spinocerebellar ataxia type 3 (Machado-Joseph disease) [74–76].
Machado-Joseph disease, the most common autosomal dominant ataxia worldwide [77, 78], belongs to the group of polyglutamine disorders, which also includes Huntington’s disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxias types 1, 2, 3, 6, 7, and 17 [79].
Due to its anti-glutamatergic properties, riluzole has potential applications in psychiatric and pediatric conditions. It has been used to treat childhood obsessive-compulsive disorder and is being explored as adjunct therapy with risperidone in children exhibiting irritability due to schizophrenia [80, 81] or autism spectrum disorders [82]. By suppressing excess glutamate, riluzole may also prevent memory impairment in the elderly and regulate neurotransmission in mood and anxiety disorders, showing antidepressant-like effects [83, 84].
In multiple sclerosis, riluzole mitigates excitotoxicity by modulating abnormal glutamate transmission [85], while in spinal muscular atrophy—a condition also influenced by glutamate toxicity—it is a potential therapeutic agent [86]. Moreover, it is being evaluated as a pharmacological option for acute spinal cord injury and early cervical myelopathy [87, 88].
Combining riluzole with antioxidants such as vitamin E, vitamin C, or coenzyme Q10 [89], or with formulations containing L-methionine, vitamin E, and selenium, may provide synergistic benefits in ALS. Creatine, with both antioxidant and neuroprotective effects, can support mitochondrial function [90], while lithium has also been noted to slow ALS progression [68].
Pain management in ALS (Lou Gehrig’s disease) may involve nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, or antispastic agents such as Baclofen and Dantrolene [91]. Additional investigational agents that may hold promise in ALS management include Memantine, Nimesulide, and Gabapentin [17].
ALS is the most devastating neurodegenerative condition affecting both upper and lower motor neurons. Its pathogenesis is multifactorial, involving genetic mutations, oxidative stress, glutamate excitotoxicity, deficiencies in trophic factors, autoimmune mechanisms, protein aggregation, inflammation, cytoskeletal disruptions, and viral infections. Riluzole remains the cornerstone of pharmacotherapy, providing neuroprotection and symptom modulation in ALS. Beyond ALS, its glutamate-modulating properties extend its utility to various neurodegenerative, psychiatric, and developmental disorders.
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