title: Activation of peroxisome proliferator-activated receptor-γ by a 12/15-lipoxygenase product of arachidonic acid: a possible neuroprotective effect in the brain after experimental intracerebral hemorrhage.
abstract: OBJECTIVE In this study, the authors investigated the involvement of 15( S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in the regulation of peroxisome proliferator-activated receptor-γ (PPARγ) after intracerebral hemorrhage (ICH) and its effects on hemorrhage-induced inflammatory response and oxidative stress in an experimental rodent model. METHODS To simulate ICH in a rat model, the authors injected autologous whole blood into the right striatum of male Sprague-Dawley rats. The distribution and expression of 12/15-lipoxygenase (12/15-LOX) were determined by immunohistochemistry and Western blot analysis, respectively. Immunofluorescent double labeling was used to study the cellular localization of 12/15-LOX, and 15(S)-HETE was measured with a 15(S)-HETE enzyme immunoassay kit. Neurological deficits in the animals were assessed through behavioral testing, and apoptotic cell death was determined with terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling. RESULTS Rats with ICH had increased expression of 12/15-LOX predominantly in neurons and also in oligodendrocytes, astrocytes, and microglia. Moreover, ICH elevated production of 15(S)-HETE in the brain area ipsilateral to the blood injection. The PPARγ agonist, exogenous 15(S)-HETE, significantly increased PPARγ protein levels and increased PPARγ-regulated gene (i.e., catalase) expression in the ICH rats. Reduced expression of the gene for the proinflammatory protein nuclear factor κB coincided with decreased neuron damage and improved functional recovery from ICH. A PPARγ antagonist, GW9662, reversed the effects of exogenous 15(S)-HETE on the PPARγ-regulated genes. CONCLUSIONS The induction of 15(S)-HETE during simulated ICH suggests generation of endogenous signals of neuroprotection. The effects of exogenous 15(S)-HETE on brain hemorrhage-induced inflammatory responses and oxidative stress might be mediated via PPARγ.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang; and.
authors.forename: Ruobing
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang; and.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang; and.
authors.forename: Weishan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang; and.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang; and.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Tang
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000502:physiology*; D001921:Brain; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology / Q000502:physiology*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D000066829:Neuroprotection; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: C475064:12-15-lipoxygenase; D006893:Hydroxyeicosatetraenoic Acids; D047495:PPAR gamma; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: 12/15-LOX = 12/15-lipoxygenase; 12/15-lipoxygenase; 15(S)-HETE = 15(S)-hydroxyeicosatetraenoic acid; AA = arachidonic acid; CD11b = cluster of differentiation molecule 11B; DMSO = dimethyl sulfoxide; GFAP = glial fibrillary acidic protein; ICH = intracerebral hemorrhage; MBP = myelin basic protein; NF-κB = nuclear factor κB; PBS = phosphate-buffered saline; PPARγ = proliferator-activated receptor-γ; TUNEL = terminal deoxynucleotidyl transferase–mediated biotinylated dUTP nick-end labeling; intracerebral hemorrhage; peroxisome proliferator-activated receptor-γ; rat; vascular disorders