The Role of Excitotoxicity in Neurodegenerative Disease
Abstract
Glutamic acid is the principal excitatory neurotransmitter in the mammalian central nervous system. Glutamic acid binds to a variety of excitatory amino acid receptors, which are ligand-gated ion channels. It is activation of these receptors that leads to depolarisation and neuronal excitation. In normal synaptic functioning, activation of excitatory amino acid receptors is transitory. However, if, for any reason, receptor activation becomes excessive or prolonged, the target neurones become damaged and eventually die. This process of neuronal death is called excitotoxicity and appears to involve sustained elevations of intracellular calcium levels. Impairment of neuronal energy metabolism may sensitise neurones to excitotoxic cell death. The principle of excitotoxicity has been well-established experimentally, both in in vitro systems and in vivo, following administration of excitatory amino acids into the nervous system. A role for excitotoxicity in the aetiology or progression of several human neurodegenerative diseases has been proposed, which has stimulated much research recently. This has led to the hope that compounds that interfere with glutamatergic neurotransmission may be of clinical benefit in treating such diseases. However, except in the case of a few very rare conditions, direct evidence for a pathogenic role for excitotoxicity in neurological disease is missing. Much attention has been directed at obtaining evidence for a role for excitotoxicity in the neurolo…
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Brain injury or neurodegenerative pathologies can induce accumulation of extracellular glutamate in the brain to toxic concentrations.
“Brain injury (Ray et al., 2002) or neurodegenerative pathologies (Doble, 1999) can induce accumulation of extracellular glutamate in the brain to toxic concentrations.”
From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Doble, 1999
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- Authors
- Doble, A.
- Corresponding author
- Doble, Adam
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 1999-03
- Volume
- 81
- Issue
- 3
- Pages
- 163-221
- ISSN
- 0163-7258 (ISSN-L)
- OpenAlex
- W111663151
- Cited by
- 723
- References
- 13
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 13 · 2023: 15 · 2022: 16 · 2021: 14 · 2020: 23 · 2019: 22 · 2018: 19 · 2017: 22 · 2016: 23 · 2015: 24 · 2014: 24 · 2013: 34 · 2012: 36
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- excitotoxicity, neurodegenerative diseases, glutamate, glutamate receptors, intracellular calcium, neuronal energy metabolism, stroke, ischemic stroke, riluzole, amyotrophic lateral sclerosis, neurolathyrism, HIV-associated dementia, Parkinson's disease, Huntington's disease, mitochondrial dysfunction, neuroprotection
- MeSH terms
- Amyotrophic Lateral Sclerosis, Calcium, Humans, AIDS Dementia Complex, N-Methylaspartate, Neurotransmitter Agents, Glutamic Acid, Excitatory Amino Acids, Neurodegenerative Diseases
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