Excitotoxicity and stroke: Identifying novel targets for neuroprotection
Open accessAbstract
Excitotoxicity, the specific type of neurotoxicity mediated by glutamate, may be the missing link between ischemia and neuronal death, and intervening the mechanistic steps that lead to excitotoxicity can prevent stroke damage. Interest in excitotoxicity began fifty years ago when monosodium glutamate was found to be neurotoxic. Evidence soon demonstrated that glutamate is not only the primary excitatory neurotransmitter in the adult brain, but also a critical transmitter for signaling neurons to degenerate following stroke. The finding led to a number of clinical trials that tested inhibitors of excitotoxicity in stroke patients. Glutamate exerts its function in large by activating the calcium-permeable ionotropic NMDA receptor (NMDAR), and different subpopulations of the NMDAR may generate different functional outputs, depending on the signaling proteins directly bound or indirectly coupled to its large cytoplasmic tail. Synaptic activity activates the GluN2A subunit-containing NMDAR, leading to activation of the pro-survival signaling proteins Akt, ERK, and CREB. During a brief episode of ischemia, the extracellular glutamate concentration rises abruptly, and stimulation of the GluN2B-containing NMDAR in the extrasynaptic sites triggers excitotoxic neuronal death via PTEN, cdk5, and DAPK1, which are directly bound to the NMDAR, nNOS, which is indirectly coupled to the NMDAR via PSD95, and calpain, p25, STEP, p38, JNK, and SREBP1, which are further downstream. This review aims to provide a comprehensive summary of the literature on excitotoxicity and our perspectives on how the new generation of excitotoxicity inhibitors may succeed despite the failure of the previous generation of drugs.
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ROCK can phosphorylate and activate PTEN, a negative regulator of PI3K/Akt, initiating apoptosis through released Akt suppression of proapoptotic Bcl-2 family proteins.
“ROCK can phosphorylate and activate phosphatase and tensin homologue (PTEN), which is a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway initiating apoptosis through released Akt suppression of proapoptotic Bcl-2 family proteins [129].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [129]
Section 3.1.1 states that PTEN terminates PI3K–Akt signaling and mediates apoptotic effects. Section 3.1 says Akt inhibits the proapoptotic BCL-2 family member BAD. Neither passage supports the claim that ROCK phosphorylates and activates PTEN; the copy describes NMDAR-related regulation of PTEN instead. Page numbers were not available in the indexed passages. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe antiapoptotic effects of Rac are antagonized by RhoA/ROCK signaling through downstream ROCK targets involved in both mitochondrial-dependent intrinsic and death receptor-dependent extrinsic apoptotic pathways.
“The antiapoptotic effects of Rac are antagonized by RhoA/ROCK signaling through a number of downstream ROCK targets involved in both mitochondrial-dependent intrinsic apoptotic pathways and death receptor-dependent extrinsic apoptotic pathways.”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [129]
Section 3.1 discusses Akt-mediated neuronal survival and uses “rac” as an alternative name for Akt, not as the Rac in the claimed Rac–RhoA/ROCK interaction. Searches for RhoA, ROCK, and death receptor-dependent extrinsic apoptosis found no passage in our copy addressing that interaction or the claimed downstream pathways. The available passages therefore do not verify the claim. (LLM, conf=0.75)
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- Authors
- Lai, T. W., Zhang, S., & Wang, Y. T.
- Affiliations
- China Medical University (TW)
- University of British Columbia (CA)
- Corresponding author
- Lai, Ted Weita
- Wang, Yu Tian
- Venue
- Progress in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 115
- Pages
- 157-188
- ISSN
- 0301-0082 (ISSN-L)
- OpenAlex
- W2083004303
- Cited by
- 1,106
- References
- 20
- Citations by year
- 2026: 52 · 2025: 84 · 2024: 87 · 2023: 89 · 2022: 118 · 2021: 115 · 2020: 104 · 2019: 84 · 2018: 108 · 2017: 91 · 2016: 66 · 2015: 77 · 2014: 29
- FWCI
- 5.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Progress in Neurobiology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Research Council of Taiwan (NSC100-2632-B-039-001-MY3, NSC102-2321-B-039-008)
- China Medical University (CMU101-N2-06)
- Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004)
- Canadian Institute for Health Research
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- excitotoxicity, stroke, neuroprotection, glutamate, NMDA receptor, GluN2A, GluN2B, extrasynaptic NMDA receptors, ischemia, neuronal cell death, Akt signaling, ERK signaling, CREB signaling, PTEN, cyclin-dependent kinase 5, DAPK1, neuronal nitric oxide synthase, PSD-95, calpain, p25, STEP, p38 MAPK, JNK, SREBP1
- MeSH terms
- Animals, Brain Injuries, Humans, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Neuroprotective Agents, Excitatory Amino Acids, Neurotoxicity Syndromes, Stroke
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