Abstract��
OBJECTIVE To investigate the protective effect of fenofibrate (Fen) on acute focal cerebral ischemia reperfusion injury in mice and its mechanisms. METHODS Cerebral ischemia was induced by middle cerebral artery occlusion in mice for 90min and then reperfusion. Fen (10�� 80 mg��kg-1) was intragastrically administered at the same time of reperfusion and 2 h after reperfusion respectively. The neurological deficit score��infarct volume and brain edema degree were determined 24 h after reperfusion. At the same time the expression of PPAR�� mRNA in brain tissue was measured by real-time RT-PCR. The contents of maiondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in the brain tissue were measured by biochemical assay. The disruption of blood-brain barrier��BBB��was evaluated by the extravasations of Evans Blue (EB). MK886�� an antagonist of PPAR�� receptor�� was used to investigate the involvement of PPAR�� in the protective effect of Fen. RESULETS Fen (80 mg��kg-1) ameliorated neurological function�� reduced infarct volume�� attenuated brain edema degree�� decreased the extravasations of EB�� increased the expression of PPAR�� mRNA�� and attenuated the lipid peroxidation in brain tissues. MK886 abolished the protective effect of Fen. CONCLUSION Fen has protective effect against acute focal cerebral ischemia reperfusion injury in mice by increasing the expression of PPAR�� mRNA and reducing lipid peroxidation in brain tissue.
MA Ang,
ZHOU Yu-*,
YANG Li-Chao etc
.The Protective Effect of Fenofibrate on Acute Focal Cerebral Ischemia Reperfusion Injury in Mice[J] Chinese Pharmaceutical Journal, 2012,V47(13): 1042-1047
��
[1]
SENDEROWICA A M. The cell cycle as a target for cancer therapy�� basic and clinical findings with the molecule inhibitors flavopiridol and UCN-01 [J]. Oncologists�� 2002�� 7�� 12-19.[2] ZHAI S�� SENDEROWICZ A M�� SAUSVILLE E A�� et al. Flavopiridol�� a novel cyclin-dependent kinase inhibitor�� in clinical development [J]. Ann Pharmacol�� 2002�� 36�� 905-911.[3] CARLSON B A�� DUBAY M M�� SAUSVILLE E A�� et al. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells [J]. Cancer Res�� 1996�� 56�� 2973-2978.[4] BRUSSELBACH S�� NETTELBECK D M�� SEDLACEK H H�� et al. Cell cycle-independent induction of apoptosis by the antitumor drug flavopiridol in endothelial cells [J]. Int J Cancer�� 1998�� 77�� 146-152.[5] KERR J S�� WEXLER R S�� MOUSA S A�� et al. Novel small molecular alpha v integrin antagonists�� comparative anti-cancer efficacy with known angiogensis inhibitors [J]. Anticancer Res�� 1999�� 19�� 959-968.[6] LIN G�� CUI Y Y�� LIU X Q�� et al. Species differences in the in vitro metabolic activation of the hepatotoxic pyrrolizidine alkaloid clivorine [J]. Chem Res Toxicol�� 2002��15(11)��1421-1428.[7] HAGENAUER B, SALAMON A, THALHAMMER T, et al. In Vitro Glucuronidation of the cyclin-dependent kinase inhibitor flavopiridol by rat and human liver microsomes: involvement of UDP-glucuronosyl transferases 1A1 and 1A9 [J]. Drug Metab Dispos, 2001, 29(4):407-414.[8] JOSEPH, T B, WANG S W J, LIU X, et al. Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms [J]. Mol Pharm, 2007�� 4(6): 883-894.[9] LIU X�� TAM V H�� HU M. Disposition of flavonoids via enteric recycling�� determination of the UDP-glucuronosyltransferase isoforms responsible for the metabolism of flavonoids in intact caco-2 TC7 cells using siRNA [J]. Mol Pharm�� 2007��4(6)��873-882.[10] TANG L, SINGH R, LIU Z, et al. Structure and concentration changes affect characterization of UGT isoform-specific metabolism of isoflavones [J]. Mol Pharm, 2009�� 6(5): 1466-1482.[11] ZHANG L�� LIN G�� ZUO Z. Position preference on glucuronidation of mono-hydroxylflavones in human intestine [J]. Life Sci�� 2006�� 78(24)��2772-2780.[12] KAHN M E S, SENDEROWICZ A, SAUSVILLE E A, et al. Possible Mechanisms of Diarrheal Side Effects Associated with the Use of a Novel Chemotherapeutic Agent, Flavopiridol[J]. Clin Cancer Res, 2001, 7��2��: 343-349.
[2]
NAGEL S�� SU Y�� HORSTMANN S�� et al. Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat��effects on BBB breakdown and MMP expression in the acute and subacute phase[J]. Brain Res�� 2008�� 1188��198-206.[2] NN I�� GREEN S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J]. Nature�� 1990�� 347��6294����645-650.[3] BERGER J P�� AKIYAMA T E�� MEINKE P T. PPARs��therapeutic targets for metabolic disease[J]. Trends Pharmacol Sci�� 2005�� 26��5����244-251.[4] CHEN X R�� BESSON V C�� PALMIER B�� et al. Neurological recovery-promoting�� anti-inflammatory�� and anti-oxidative effects afforded by fenofibrate�� a PPAR alpha agonist�� in traumatic brain injury[J]. J Neurotrauma�� 2007�� 24��7����1119-1131.[5] DEPLANQUE D�� GELE P�� PETRAULT O�� et al. Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment[J]. J Neurosci�� 2003�� 23��15����6264-6271. [6] ZHANG Y L��YANG J Q. Effects of fenofibrate on global cerebral ischemia / reperfusion injury in rats[J] Chin Pharmacol Bull (�й�ҩ��ѧͨ��)��2010�� 26��3��:320-324[7] MAO Y�� YANG G Y�� ZHOU L F�� et al. Focal cerebral ischemia in the mouse��description of a model and effects of permanent and temporary occlusion[J]. Brain Res Mol Brain Res�� 1999�� 63��2����366-370.[8] YANG L C�� YANG W S�� ZHOU Y�� et al. Protective effect of Oleoylethanolamide on focal cerebral ischemia in mice [J]. Chin Pharmacol Bull (�й�ҩ��ѧͨ��)��2009��25��9����1219-1223.[9] LONGA E Z�� WEINSTEIN P R�� CARLSON S�� et al. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke�� 1989�� 20��1����84-91.[10] STRBIAN D�� DURUKAN A�� PITKONEN M�� et al. The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia[J]. Neuroscience�� 2008�� 153��1����175-181.[11] MYSIOREK C�� CULOT M�� DEHOUCK L�� et al. Peroxisome-proliferator-activated receptor-alpha activation protects brain capillary endothelial cells from oxygen-glucose deprivation-induced hyperpermeability in the blood-brain barrier[J]. Curr Neurovasc Res�� 2009�� 6��3����181-193.[12] SUN Y�� ALEXANDER S P�� GARLE M J�� et al. Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism[J]. Br J Pharmacol�� 2007�� 152��5����734-743.[13] BORDET R�� OUK T�� PETRAULT O�� et al. PPAR��a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases[J]. Biochem Soc Trans�� 2006�� 34��Pt 6����1341-1346.[14] PIALAT J B�� CHO T H�� BEUF O�� et al. MRI monitoring of focal cerebral ischemia in peroxisome proliferator-activated receptor (PPAR)-deficient mice[J]. NMR Biomed�� 2007�� 20��3����335-342.[15] COLLINO M�� ARAGNO M�� MASTROCOLA R�� et al. Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion��effects of the PPAR-alpha agonist WY14643[J]. Free Radic Biol Med�� 2006�� 41��4����579-589.[16] CHENG G�� ZHANG X�� GAO D�� et al. Resveratrol inhibits MMP-9 expression by up-regulating PPAR alpha expression in an oxygen glucose deprivation-exposed neuron model[J]. Neurosci Lett�� 2009�� 451��2����105-108.[17] NITA D A�� NITA V�� SPULBER S�� et al. Oxidative damage following cerebral ischemia depends on reperfusion - a biochemical study in rat[J]. J Cell Mol Med�� 2001�� 5��2����163-170.[18] CHRISSOBOLIS S�� MILLER A A�� DRUMMOND G R�� et al. Oxidative stress and endothelial dysfunction in cerebrovascular disease[J]. Front Biosci�� 2011�� 16��1733-1745.[19] GAO M�� SHI L L�� ZHANG H A�� et al. Therapeutic effect of edaravone in transient global brain ischemia /reperfusion rats [J]. Chin Pharm J (�й�ҩѧ��־) �� 2011�� 46(12) ��932-936.[20] WANG G�� LIU X�� GUO Q�� et al. Chronic treatment with fibrates elevates superoxide dismutase in adult mouse brain microvessels[J]. Brain Res�� 2010�� 1359��247-255.[21] BLANQUART C�� BARBIER O�� FRUCHART J C�� et al. Peroxisome proliferator-activated receptors��regulation of transcriptional activities and roles in inflammation[J]. J Steroid Biochem Mol Biol�� 2003�� 85��2-5����267-273.
2012, Vol. 47 