Mechanism of Action of Riluzole in Amyotrophic Lateral Sclerosis
Riluzole's exact mechanism of action in ALS remains unknown, but it is thought to reduce motor neuron damage primarily through inhibition of glutamate release and modulation of sodium channel activity. 1
Primary Proposed Mechanisms
Glutamate-mediated excitotoxicity reduction is the most widely accepted mechanism, whereby riluzole inhibits presynaptic glutamate release, thereby protecting motor neurons from excitotoxic damage 2. This effect occurs at clinically relevant concentrations (plasma levels 1-2 μM, with 3-4 fold higher brain tissue concentrations) 3.
Sodium channel modulation represents another key mechanism, with riluzole inhibiting both persistent and fast sodium currents in motor neurons 3. The inhibition of persistent Na+ current and repetitive neuronal firing occurs at the lowest effective doses (<1 μM), making this one of the most pharmacologically relevant actions 3.
Additional Neuroprotective Effects
Beyond glutamate modulation, riluzole demonstrates multiple effects on neuronal function across a wide dose range:
- Potentiation of calcium-dependent potassium currents occurs at low micromolar concentrations, contributing to neuronal membrane stabilization 3
- Inhibition of voltage-gated calcium channels reduces calcium-mediated excitotoxicity at higher therapeutic concentrations 3
- Promotion of neuronal survival factors has been demonstrated in preclinical models, though the clinical relevance remains uncertain 3
Neuroprotection Beyond ALS
Riluzole's neuroprotective properties extend to other neurological injuries. In spinal cord injury models, riluzole attenuates secondary injury pathways, increases neural tissue preservation, and improves neurobehavioral outcomes compared to placebo and other sodium channel-blocking medications 4. These findings led to the ongoing RISCIS phase IIb/III trial investigating riluzole in acute traumatic spinal cord injury 4.
Clinical Pharmacology Considerations
The FDA label explicitly states that "the mechanism by which riluzole exerts its therapeutic effects in patients with ALS is unknown," emphasizing the gap between proposed mechanisms and definitive understanding 1. Despite this uncertainty, riluzole remains the only treatment proven to modestly extend survival in ALS patients, with a well-established safety profile over two decades of clinical use 2, 5.
Riluzole is primarily metabolized by hepatic cytochrome CYP1A2 and extrahepatic CYP1A1 6. However, genetic polymorphisms in these enzymes do not appear to significantly influence riluzole plasma levels or metabolic profiles in ALS patients 6.
Clinical Efficacy Context
The 100 mg daily dose demonstrates the optimal benefit-to-risk ratio, producing a 35% reduction in mortality risk (adjusted hazard ratio 0.65, p=0.002) after 18 months of treatment 5. This survival benefit occurs without measurable improvement in functional scales, muscle strength, or respiratory function 5, suggesting that riluzole's neuroprotective effects slow disease progression at the cellular level rather than reversing established motor neuron loss.
Critical Limitations
No functional outcome measures discriminate between riluzole-treated and placebo groups 5, meaning patients experience extended survival without measurable improvement in strength, function, or quality of life during treatment. This underscores that riluzole is a disease-modifying agent that slows progression rather than a symptomatic treatment 2.
The most common adverse effects—asthenia, dizziness, gastrointestinal disorders, and elevated liver enzymes—occur in a dose-dependent manner, with the 200 mg dose showing the highest incidence 5. Regular monitoring of liver function is essential during riluzole therapy 5.