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J Psychiatr Res. 2016 May;76:59-65. doi: 10.1016/j.jpsychires.2016.02.001. Epub 2016 Feb 6.

Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment.

Author information

1
Departments of Pharmacology & Psychiatry, University of Toronto, Toronto, Ontario, M5S1A8, Canada. Electronic address: helenakim0913@gmail.com.
2
Departments of Pharmacology & Psychiatry, University of Toronto, Toronto, Ontario, M5S1A8, Canada. Electronic address: cameron.isaacs.trepanier@gmail.com.
3
Departments of Pharmacology & Psychiatry, University of Toronto, Toronto, Ontario, M5S1A8, Canada. Electronic address: nikaelmi@gmail.com.
4
Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, United States. Electronic address: sir@mail.nih.gov.
5
Departments of Pharmacology & Psychiatry, University of Toronto, Toronto, Ontario, M5S1A8, Canada; Centre of Addiction and Mental Health, Toronto, Ontario, M5T1R8, Canada. Electronic address: ana.andreazza@utoronto.ca.

Abstract

Chronic N-methyl-d-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder.

KEYWORDS:

Excitotoxicity; Lipid peroxidation; Lithium; Mitochondria; NMDA

PMID:
26894301
PMCID:
PMC5843818
DOI:
10.1016/j.jpsychires.2016.02.001
[Indexed for MEDLINE]
Free PMC Article

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