ANIMAL MODEL OF EXCITOXICITY WITH NEUROINFLAMMATION Excitotoxicity is thought to contribute to brain damage in human diseases, including Alzheimer disease and bipolar disorder. We developed an animal model of excitotoxicity, the rat to which the glutamate receptor agonist, N-methyl-D-aspartate (NMDA), is administered daily for 21 days. The brain of this rat demonstrated upregulated markers of AA metabolism, and increased neuroinflammatory markers (interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase). This model might be used to develop drugs that suppress the upregulated arachidonic metabolism of excitotoxicity-neuroinflammation, and to further understand pathological mechanisms (Ref.3,1). ARACHIDONIC AND DOCOSAHEXAENOIC ACID METABOLITES IN ISCHEMIC BRAIN Biologically active metabolites of AA and docosahexaenoic acid (DHA) arise during brain ischemia and other brain insults, and can influence cell death and neuroprotection. We used reversed phase liquid chromatography/tandem mass spectrometry to quantify their production in rat brain subjected to cerebral ischemia and removed after head-focused microwave irradiation to stop postmortem metabolism. Brain AA, DHA and docosapentaenoic acid (n-6) concentrations were increased 18-, 5- and 4-fold compared to control values, respectively. Prostaglandin E2 and D2 were not detected in control brain. Concentrations of thromboxane B2, E2/D2-isoprostanes, 5-HETE, 5-oxo-ETE, and 12-HETE (other eicosanoids) were significantly elevated by ischemia, as was 17-hydroxy-DHA, the immediate precursor of neuroprotectin D1. These alterations in the balance of lipid mediators likely mediate brain injury and recovery (Ref.2).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000151-02
Application #
7963872
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$265,582
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Taha, Ameer Y; Hennebelle, Marie; Yang, Jun et al. (2018) Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid. Prostaglandins Leukot Essent Fatty Acids 138:71-80
Taha, Ameer Y; Chang, Lisa; Chen, Mei (2016) Threshold changes in rat brain docosahexaenoic acid incorporation and concentration following graded reductions in dietary alpha-linolenic acid. Prostaglandins Leukot Essent Fatty Acids 105:26-34
Blanchard, Helene C; Taha, Ameer Y; Rapoport, Stanley I et al. (2015) Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders. Prostaglandins Leukot Essent Fatty Acids 96:25-30
Bondi, Corina O; Taha, Ameer Y; Tock, Jody L et al. (2014) Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency. Biol Psychiatry 75:38-46
Primiani, Christopher T; Ryan, Veronica H; Rao, Jagadeesh S et al. (2014) Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging. PLoS One 9:e110972
Bhattacharjee, Abesh Kumar; White, Laura; Chang, Lisa et al. (2012) Bilateral common carotid artery ligation transiently changes brain lipid metabolism in rats. Neurochem Res 37:1490-8
Kellom, Matthew; Basselin, Mireille; Keleshian, Vasken L et al. (2012) Dose-dependent changes in neuroinflammatory and arachidonic acid cascade markers with synaptic marker loss in rat lipopolysaccharide infusion model of neuroinflammation. BMC Neurosci 13:50
Kim, Hyung-Wook; Cheon, Yewon; Modi, Hiren R et al. (2012) Effects of chronic clozapine administration on markers of arachidonic acid cascade and synaptic integrity in rat brain. Psychopharmacology (Berl) 222:663-74
Taha, Ameer Y; Basselin, Mireille; Ramadan, Epolia et al. (2012) Altered lipid concentrations of liver, heart and plasma but not brain in HIV-1 transgenic rats. Prostaglandins Leukot Essent Fatty Acids 87:91-101
Cheon, Yewon; Kim, Hyung-Wook; Igarashi, Miki et al. (2012) Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A(2)-VIA (iPLA(2)?)-knockout mice. Biochim Biophys Acta 1821:1278-86

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