title: 12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain.
abstract: The enzyme 12/15-lipoxygenase (LOX) oxidizes various free fatty acids, including arachidonic acid (AA). In the brain, the principal 12/15-LOX metabolites of AA are 12(S)-HETE and 15(S)-HETE. PPARγ is a nuclear receptor whose activation is neuroprotective through its anti-inflammatory properties. In this study, we investigate the involvement of 12(S)- and 15(S)-HETE in the regulation of PPARγ following cerebral ischemia and their effects on ischemia-induced inflammatory response. We show here the increased expression of 12/15-LOX, predominantly in neurons, and elevated production of 12(S)-HETE and 15(S)-HETE in ischemic brain. The exogenous 12(S)- and 15(S)-HETE increase PPARγ protein level, nuclear translocation, and DNA-binding activity in ischemic rats, suggesting the activation of PPARγ. This effect was further confirmed by showing the increased PPARγ transcriptional activity in primary cortical neurons when incubated with 12(S)- or 15(S)-HETE. Moreover, both 12(S)- and 15(S)-HETE potently inhibited the induction of nuclear factor-κB, inducible NO synthase, and cyclooxygenase-2 in ischemic rats, and elicited neuroprotection. The reversal of the effects of 12(S)- and 15(S)-HETE on pro-inflammatory factors by PPARγ antagonist GW9662 indicated their actions were mediated via PPARγ. Thus, the induction of 12(S)- and 15(S)-HETE during brain ischemia suggests that endogenous signals of neuroprotection may be generated.
authors.affiliation: Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, People's Republic of China. Electronic address: sunli_2000@hotmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, People's Republic of China.
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Xu
authors.affiliation: Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liang
authors.affiliation: Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C475064:12-15-lipoxygenase; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D006893:Hydroxyeicosatetraenoic Acids; D047495:PPAR gamma; D016718:Arachidonic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: brain ischemia; hydroxyeicosatetraenoic acid; peroxisome proliferator-activated receptor γ