The DOI matches its Crossref record; 202 of the 202 references it cites were found in a registry or an index.
A Review of the Neural Mechanisms of Action and Clinical Efficiency of Riluzole in Treating Amyotrophic Lateral Sclerosis: What have we Learned in the Last Decade?: Neural Mechanisms of Action and Clinical Efficiency of Riluzole in Treating ALS
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of adults which preferentially attacks the neuromotor system. Riluzole has been used as the only approved treatment for amyotrophic lateral sclerosis since 1995, but its mechanism(s) of action in slowing the progression of this disease remain obscure. Searching PubMed for "riluzole" found 705 articles published between January 1996 and June 2009. A systematic review of this literature found that riluzole had a wide range of effects on factors influencing neural activity in general, and the neuromotor system in particular. These effects occurred over a large dose range (<1 μM to >1 mM). Reported neural effects of riluzole included (in approximate ascending order of dose range): inhibition of persistent Na(+) current = inhibition of repetitive firing < potentiation of calcium-dependent K(+) current < inhibition of neurotransmitter release < inhibition of fast Na(+) current < inhibition of voltage-gated Ca(2+) current = promotion of neuronal survival or growth factors < inhibition of voltage-gated K(+) current = modulation of two-pore K(+) current = modulation of ligand-gated neurotransmitter receptors = potentiation of glutamate transporters. Only the first four of these effects commonly occurred at clinically relevant concentrations of riluzole (plasma levels of 1-2 μM with three- to four-fold higher concentrations in brain tissue). Treatment of human ALS patients or transgenic rodent models of ALS with riluzole most commonly produced a modest but significant extension of lifespan. Riluzole treatment was well tolerated in humans and animals. In animals, despite in vitro evidence that riluzole may inhibit rhythmic motor behaviors, in vivo administration of riluzole produced relatively minor effects on normal respiration parameters, but inhibited hypoxia-induced gasping. This effect may have implications for the management of hypoventilation and sleep-disordered breathing during end-stage ALS in humans.
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“It is a voltagesensitive sodium channel blocker with high affinity for inactivated channels resulting in the inhibition of high-frequency neuronal firing.”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Bellingham, 2011
In the citing paper
“As a proposed main mechanism, riluzole reduces glutamatergic neurotransmission by blocking NMDA receptors, increasing synaptic AMPA receptor trafficking and the clearance of glutamate via glutamate transporters.”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Bellingham, 2011
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Oppenheim, R. W. (1991) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.14.030191.002321 · Cited by 3,084
A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis
Bensimon, G., Lacomblez, L., & Meininger, V. (1994) · New England Journal of Medicine · doi:10.1056/nejm199403033300901 · Cited by 2,239
Pre-Bötzinger Complex: a Brainstem Region that May Generate Respiratory Rhythm in Mammals
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Dose-ranging study of riluzole in amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis/Riluzole Study Group II, Lacomblez, L., Bensimon, G., Meininger, V., Leigh, P. N., & Guillet, P. (1996) · The Lancet · doi:10.1016/s0140-6736(96)91680-3 · Cited by 1,303
UNRAVELING THE MECHANISMS INVOLVED IN MOTOR NEURON DEGENERATION IN ALS
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Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)
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Molecular Diversity of K+ Channels
COETZEE, W. A., AMARILLO, Y., CHIU, J., CHOW, A., LAU, D., McCORMACK, T., MORENA, H., NADAL, M. S., OZAITA, A., POUNTNEY, D., et al. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb11293.x · Cited by 1,095
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Cited by
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ALS clinical trials review: 20 years of failure. Are we any closer to registering a new treatment?
Petrov, D., Mansfield, C., Moussy, A., & Hermine, O. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00068 · Cited by 451
An astroglial basis of major depressive disorder? An overview
Wang, Q., Jie, W., Liu, J., Yang, J., & Gao, T. (2017) · Glia · doi:10.1002/glia.23143 · Cited by 222
Sartori, S. B., & Singewald, N. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107402 · Cited by 236
Pun, F. W., Liu, B. H. M., Long, X., Leung, H. W., Leung, G. H. D., Mewborne, Q. T., Gao, J., Shneyderman, A., Ozerov, I. V., Wang, J., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.914017 · Cited by 115
“…riluzole has a wide range of neural effects, including inhibition of persistent and fast sodium currents, suppression of neurotransmitter release, diminishment of voltage-gated calcium and potassium currents, and potentiation of calcium-dependent potassium current (Doble, 1996; Bellingham, 2011).”
BackgroundSynaptic dysfunction and altered excitability in C9ORF72 ALS/FTD
Starr, A., & Sattler, R. (2018) · Brain Research · doi:10.1016/j.brainres.2018.02.011 · Cited by 78
Metadata
- Authors
- Bellingham, M. C.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- Bellingham, Mark C.
- ORCID
- Bellingham, Mark C.
- Venue
- CNS Neuroscience & Therapeutics
- Publisher
- Wiley
- Published
- 2011-01-17
- Volume
- 17
- Issue
- 1
- Pages
- 4-31
- ISSN
- 1755-5930 (ISSN-L)
- PMC
- PMC6493865
- OpenAlex
- W1590729586
- Cited by
- 388
- References
- 202
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 19 · 2023: 23 · 2022: 34 · 2021: 23 · 2020: 31 · 2019: 23 · 2018: 29 · 2017: 34 · 2016: 23 · 2015: 28 · 2014: 22 · 2013: 22 · 2012: 22
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- CNS Neuroscience & Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- riluzole, amyotrophic lateral sclerosis, mechanism of action, sodium channel inhibition, calcium-activated potassium current, neurotransmitter release, glutamate transporters, neuronal survival, lifespan extension, hypoventilation, sleep-disordered breathing, neuroprotection
- MeSH terms
- Adult, Aged, Amyotrophic Lateral Sclerosis, Animals, Brain, Dose-Response Relationship, Drug, Humans, Middle Aged, Motor Neurons, Excitatory Amino Acid Antagonists, Neuroprotective Agents, Riluzole
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