title: Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment.
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.
authors.affiliation: Departments of Pharmacology & Psychiatry, University of Toronto, Toronto, Ontario, M5S1A8, Canada. Electronic address: helenakim0913@gmail.com.
authors.forename: Helena K
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Departments of Pharmacology & Psychiatry, University of Toronto, Toronto, Ontario, M5S1A8, Canada. Electronic address: cameron.isaacs.trepanier@gmail.com.
authors.forename: Cameron
authors.initials: C
authors.lastname: Isaacs-Trepanier
authors.affiliation: Departments of Pharmacology & Psychiatry, University of Toronto, Toronto, Ontario, M5S1A8, Canada. Electronic address: nikaelmi@gmail.com.
authors.forename: Nika
authors.initials: N
authors.lastname: Elmi
authors.affiliation: 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.
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
authors.affiliation: 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.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Andreazza
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects*; D008094:Lithium / Q000627:therapeutic use*; D008297:Male; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009097:Multienzyme Complexes / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D018709:Statistics, Nonparametric
chemical_list: D000447:Aldehydes; D000928:Antidepressive Agents; D018690:Excitatory Amino Acid Agonists; D009097:Multienzyme Complexes; C075750:8-epi-prostaglandin F2alpha; D016202:N-Methylaspartate; D008094:Lithium; D015237:Dinoprost; C027576:4-hydroxy-2-nonenal
keywords: Excitotoxicity; Lipid peroxidation; Lithium; Mitochondria; NMDA