Blockade of quinolinic acid-induced neurotoxicity by pyruvate is associated with inhibition of glial activation in a model of Huntington’s disease
Abstract
In this study, we have examined the mechanisms involved in pyruvate-mediated neuroprotection against quinolinic acid (QA)-induced striatal damage. QA injection into the striatum caused widespread neuronal damage and extensive areas of lesions in core and penumbra. The involvement of oxidative-mediated striatal damage was suggested by increased expressions of peroxynitrite, marked lipid peroxidation, and formation of DNA oxidative damage products. Administration of pyruvate, a glycolysis end product with antioxidant activity, significantly reduced QA-mediated striatal lesions, neuronal degeneration, and oxidative damage, whereas another energy substrate, lactate, was ineffective against oxidative damage and only partially effective in reducing lesions and neuronal degeneration. Treatment with the iNOS inhibitor aminoguanidine attenuated QA-mediated striatal lesions and reduced oxidative damage, indicating that iNOS activation may be involved in the striatal oxidative damage induced by QA. A role for glial cells in mediating oxidative damage was suggested because pyruvate blocked the expression of iNOS and nitrotyrosine in activated microglia and astrocytes in QA-injected striatum. These data suggest that pyruvate reduces oxidative free radical damage in QA-injected striatum and could have clinical utility in the treatment of Huntington's disease (HD).
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Neurotoxicity in neurons is triggered by overstimulation of NMDA receptors, leading to disruptions in intracellular Ca2+ homeostasis and free radical formation.
“Neurotoxicity in neurons is triggered by the overstimulation of NMDA receptors, leading to disruptions in intracellular Ca2+ homeostasis and free radical formation [53,54].”
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InfluentialBeneficial Effects of Sodium or Ethyl Pyruvate after Traumatic Brain Injury in the Rat
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“Hence, additional research focusing on the enzymes responsible for catalyzing the production of various KP metabolites, as well as exploring potential KP enzyme inhibitors, which emerge as a promising avenue for therapeutic interventions in neurodegenerative diseases, is warranted.”
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“On the basis of our preliminary observations and prior reports characterizing QA as a signaling molecule in the brain, 26 – 29 we hypothesized that QA modulates microglial phagocytic function under AD-related stress.”
Self-citationMitochondrial Antioxidants in Neuroprotection
Fiskum, G., & Laird, M. D. (2012) · Oxidative stress and disease · doi:10.1201/b12308-26
- Authors
- Ryu, J. K., Kim, S. U., & McLarnon, J. G.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- McLarnon, James G.
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2004-05
- Volume
- 187
- Issue
- 1
- Pages
- 150-159
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2056119329
- Cited by
- 62
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Heart and Stroke Foundation of British Columbia and Yukon
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- quinolinic acid, pyruvate, neuroprotection, Huntington's disease, striatal neurotoxicity, oxidative stress, inducible nitric oxide synthase, aminoguanidine, nitrotyrosine, microglial activation, astrocyte activation, peroxynitrite, lipid peroxidation, oxidative DNA damage, lactate, glycolysis
- MeSH terms
- Animals, Disease Models, Animal, Drug Administration Routes, Enzyme Inhibitors, Guanidines, Huntington Disease, Male, Neuroglia, Stereotaxic Techniques, Tyrosine, Neostriatum, Rats, Sprague-Dawley, Quinolinic Acid, Oxidative Stress, Neuroprotective Agents, Nitric Oxide Synthase, Pyruvic Acid, Lactic Acid, Rats, Nitric Oxide Synthase Type II
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