Leonurine protects ischemia-induced brain injury via modulating SOD, MDA and GABA levels
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摘要
The present study was designed to investigate the protective effects of leonurine, a compound purified from Herba Leonuri that is active on ischemic rat behavior and cortical neurons, and explore the underlying mechanism. The general rat activity, cortical neuron morphology,superoxide dismutase(SOD), malondialdehyde(MDA), gaminobutyric acid(GABA) and glutamate decarboxylase67(GAD67) levels were measured. We found leonurine significantly improve the general activity of rats in an open-field test, which was associated with attenuated neuronal damage induced by ischemia. Moreover, serum SOD activity was significantly greater, MDA level lower in the leonurine group as compared with ischemia group.In addition, GABA content in the cerebral cortex was significantly greater in high-dose leonurine group. Correspondingly, GAD67 protein level coincided with the GABA level. Taken together, our results demonstrated that leonurine attenuated brain injury during ischemia via antioxidative and anti-excitotoxicity effects by targeting GABA and leonurine might become a useful adjuvant neuroprotective agent.
The present study was designed to investigate the protective effects of leonurine, a compound purified from Herba Leonuri that is active on ischemic rat behavior and cortical neurons, and explore the underlying mechanism. The general rat activity, cortical neuron morphology,superoxide dismutase(SOD), malondialdehyde(MDA), gaminobutyric acid(GABA) and glutamate decarboxylase67(GAD67) levels were measured. We found leonurine significantly improve the general activity of rats in an open-field test, which was associated with attenuated neuronal damage induced by ischemia. Moreover, serum SOD activity was significantly greater, MDA level lower in the leonurine group as compared with ischemia group.In addition, GABA content in the cerebral cortex was significantly greater in high-dose leonurine group. Correspondingly, GAD67 protein level coincided with the GABA level. Taken together, our results demonstrated that leonurine attenuated brain injury during ischemia via antioxidative and anti-excitotoxicity effects by targeting GABA and leonurine might become a useful adjuvant neuroprotective agent.
The present study was designed to investigate the protective effects of leonurine, a compound purified from Herba Leonuri that is active on ischemic rat behavior and cortical neurons, and explore the underlying mechanism. The general rat activity, cortical neuron morphology,superoxide dismutase(SOD), malondialdehyde(MDA), gaminobutyric acid(GABA) and glutamate decarboxylase67(GAD67) levels were measured. We found leonurine significantly improve the general activity of rats in an open-field test, which was associated with attenuated neuronal damage induced by ischemia. Moreover, serum SOD activity was significantly greater, MDA level lower in the leonurine group as compared with ischemia group.In addition, GABA content in the cerebral cortex was significantly greater in high-dose leonurine group. Correspondingly, GAD67 protein level coincided with the GABA level. Taken together, our results demonstrated that leonurine attenuated brain injury during ischemia via antioxidative and anti-excitotoxicity effects by targeting GABA and leonurine might become a useful adjuvant neuroprotective agent.
引文
1.Dirnagl U,Iadecola C,Moskowitz M A.Pathobiology of ischaemic stroke:an integrated view.Trends in Neurosciences,1999,22(9):391-397
2.Mehta S L,Manhas N,Raghubir R.Molecular targets in cerebral ischemia for developing novel therapeutics.Brains Research Reviews,2007,54(1):34-66
3.Nakka V P,Gusain A,Mehta S L,Raghubir R.Molecular mechanisms of apoptosis in cerebral ischemia:multiple neuroprotective opportunities.Molecular Neurobiology,2008,37(1):7-38
4.Aarts M M,Tymianski M.Molecular mechanisms underlying specificity of excitotoxic signaling in neurons.Current Molecular Medicine,2004,4(2):137-147
5.Takagi K,Ginsberg M D,Globus M Y,Dietrich W D,Martinez E,Kraydieh S,Busto R.Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat:correlation with histopathology.Journal of Cerebral Blood Flow and Metabolism,1993,13(4):575-585
6.Mason G F,Martin D L,Martin S B,Manor D,Sibson N R,Patel A,Rothman D L,Behar K L.Decrease in GABA synthesis rate in rat cortex following GABA-transaminase inhibition correlates with the decrease in GAD(67)protein.Brain Research,2001,914(1-2):81-91
7.Madl J E,Royer S M.Glutamate dependence of GABA levels in neurons of hypoxic and hypoglycemic rat hippocampal slices.Neuroscience,2000,96(4):657-664
8.Liu X,Pan L,Wang X,Gong Q,Zhu Y Z.Leonurine protects against tumor necrosis factor-α-mediated inflammation in human umbilical vein endothelial cells.Atherosclerosis,2012,222(1):34-42
9.Liu X H,Pan L L,Deng H Y,Xiong Q H,Wu D,Huang G Y,Gong Q H,Zhu Y Z.Leonurine(SCM-198)attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4.Free Radical Biology&Medicine,2013,54:93-104
10.Loh K P,Qi J,Tan B K,Liu X H,Wei B G,Zhu Y Z.Leonurine protects middle cerebral artery occluded rats through antioxidant effect and regulation of mitochondrial function.Stroke,2010,41(11):2661-2668
11.Wang Q H,Zhang S,Qin L M,Zhang W J,Liu F H,Xu J Q,Ma Y F,Teng K D.Yimu San improves obstetric ability of pregnant mice by increasing serum oxytocin levels and connexin 43 expression in uterine smooth muscle.Journal of Zhejiang University:Science B,2017,18(11):986-993
12.Zemke D,Smith J L,Reeves M J,Majid A.Ischemia and ischemic tolerance in the brain:an overview.Neurotoxicology,2004,25(6):895-904
13.Zádori D,Klivényi P,Szalárdy L,Fül?p F,Toldi J,Vécsei L.Mitochondrial disturbances,excitotoxicity,neuroinflammation and kynurenines:novel therapeutic strategies for neurodegenerative disorders.Journal of the Neurological Sciences,2012,322(1-2):187-191
14.Wang Y,Wan C,Yu S,Yang L,Li B,Lu T,Bi Y,Jiang J,Cui G.Upregulated expression of NF-YC contributes to neuronal apoptosis via proapoptotic protein bim in rats’brain hippocampus following middle cerebral artery occlusion(MCAO).Journal of Molecular Neuroscience,2014,52(4):552-565
15.Lo Iacono L,Gross C.Alpha-Ca2+/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice.Journal of Neuroscience:The Official Journal of the Society for Neuroscience,2008,28(24):6250-6257
16.Liu H,Zhang X,Du Y,Ji H,Li S,Li L,Xing Y,Zhang X,Dong L,Wang C,Zhao K,Ji Y,Cao X.Leonurine protects brain injury by increased activities of UCP4,SOD,CAT and Bcl-2,decreased levels of MDA and Bax,and ameliorated ultrastructure of mitochondria in experimental stroke.Brain Research,2012,1474:73-81
17.Hua J S,Li L P,Zhu X M,Wang Y J.Effects of moxibustion pretreating on SOD and MDA in the rat of global brain ischemia.Journal of Traditional Chinese Medicine,2008,28(4):289-292
18.Akman T,Guven M,Aras A B,Ozkan A,Sen H M,Okuyucu A,Kalkan Y,Sehitoglu I,Silan C,Cosar M.The neuroprotective effect of glycyrrhizic acid on an experimental model of focal cerebral ischemia in rats.Inflammation,2015,38(4):1581-1588
19.Puyal J,Ginet V,Clarke P G.Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage:a challenge for neuroprotection.Progress in Neurobiology,2013,105:24-48
20.Ahmad A S,Shah Z A,DoréS.Protective role of arginase II in cerebral ischemia and excitotoxicity.Journal of Neurology and Neuroscience,2016,7(2):88-93
21.Erd?S,Michler A,Wolff J R.GABA accelerates excitotoxic cell death in cortical cultures:protection by blockers of GABA-gated chloride channels.Brain Research,1991,542(2):254-258
22.Monnerie H,Le Roux P D.Glutamate alteration of glutamic acid decarboxylase(GAD)in GABAergic neurons:the role of cysteine proteases.Experimental Neurology,2008,213(1):145-153
23.Loh K P,Huang S H,Tan B K H,Zhu Y Z.Cerebral protection of purified Herba Leonuri extract on middle cerebral artery occluded rats.Journal of Ethnopharmacology,2009,125(2):337-343
24.Wang Z,Zhang P L,Ju Y.Effect of leonurine on the activity of creatine kinase.Journal of Asian Natural Products Research,2004,6(4):281-287
25.Qi J,Hong Z Y,Xin H,Zhu Y Z.Neuroprotective effects of leonurine on ischemia/reperfusion-induced mitochondrial dysfunctions in rat cerebral cortex.Biological&Pharmaceutical Bulletin,2010,33(12):1958-1964
26.Liu C,Yin H,Gao J,Xu X,Zhang T,Yang Z.Leonurine ameliorates cognitive dysfunction via antagonizing excitotoxic glutamate insults and inhibiting autophagy.Phytomedicine,2016,23(13):1638-1646
2.Mehta S L,Manhas N,Raghubir R.Molecular targets in cerebral ischemia for developing novel therapeutics.Brains Research Reviews,2007,54(1):34-66
3.Nakka V P,Gusain A,Mehta S L,Raghubir R.Molecular mechanisms of apoptosis in cerebral ischemia:multiple neuroprotective opportunities.Molecular Neurobiology,2008,37(1):7-38
4.Aarts M M,Tymianski M.Molecular mechanisms underlying specificity of excitotoxic signaling in neurons.Current Molecular Medicine,2004,4(2):137-147
5.Takagi K,Ginsberg M D,Globus M Y,Dietrich W D,Martinez E,Kraydieh S,Busto R.Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat:correlation with histopathology.Journal of Cerebral Blood Flow and Metabolism,1993,13(4):575-585
6.Mason G F,Martin D L,Martin S B,Manor D,Sibson N R,Patel A,Rothman D L,Behar K L.Decrease in GABA synthesis rate in rat cortex following GABA-transaminase inhibition correlates with the decrease in GAD(67)protein.Brain Research,2001,914(1-2):81-91
7.Madl J E,Royer S M.Glutamate dependence of GABA levels in neurons of hypoxic and hypoglycemic rat hippocampal slices.Neuroscience,2000,96(4):657-664
8.Liu X,Pan L,Wang X,Gong Q,Zhu Y Z.Leonurine protects against tumor necrosis factor-α-mediated inflammation in human umbilical vein endothelial cells.Atherosclerosis,2012,222(1):34-42
9.Liu X H,Pan L L,Deng H Y,Xiong Q H,Wu D,Huang G Y,Gong Q H,Zhu Y Z.Leonurine(SCM-198)attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4.Free Radical Biology&Medicine,2013,54:93-104
10.Loh K P,Qi J,Tan B K,Liu X H,Wei B G,Zhu Y Z.Leonurine protects middle cerebral artery occluded rats through antioxidant effect and regulation of mitochondrial function.Stroke,2010,41(11):2661-2668
11.Wang Q H,Zhang S,Qin L M,Zhang W J,Liu F H,Xu J Q,Ma Y F,Teng K D.Yimu San improves obstetric ability of pregnant mice by increasing serum oxytocin levels and connexin 43 expression in uterine smooth muscle.Journal of Zhejiang University:Science B,2017,18(11):986-993
12.Zemke D,Smith J L,Reeves M J,Majid A.Ischemia and ischemic tolerance in the brain:an overview.Neurotoxicology,2004,25(6):895-904
13.Zádori D,Klivényi P,Szalárdy L,Fül?p F,Toldi J,Vécsei L.Mitochondrial disturbances,excitotoxicity,neuroinflammation and kynurenines:novel therapeutic strategies for neurodegenerative disorders.Journal of the Neurological Sciences,2012,322(1-2):187-191
14.Wang Y,Wan C,Yu S,Yang L,Li B,Lu T,Bi Y,Jiang J,Cui G.Upregulated expression of NF-YC contributes to neuronal apoptosis via proapoptotic protein bim in rats’brain hippocampus following middle cerebral artery occlusion(MCAO).Journal of Molecular Neuroscience,2014,52(4):552-565
15.Lo Iacono L,Gross C.Alpha-Ca2+/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice.Journal of Neuroscience:The Official Journal of the Society for Neuroscience,2008,28(24):6250-6257
16.Liu H,Zhang X,Du Y,Ji H,Li S,Li L,Xing Y,Zhang X,Dong L,Wang C,Zhao K,Ji Y,Cao X.Leonurine protects brain injury by increased activities of UCP4,SOD,CAT and Bcl-2,decreased levels of MDA and Bax,and ameliorated ultrastructure of mitochondria in experimental stroke.Brain Research,2012,1474:73-81
17.Hua J S,Li L P,Zhu X M,Wang Y J.Effects of moxibustion pretreating on SOD and MDA in the rat of global brain ischemia.Journal of Traditional Chinese Medicine,2008,28(4):289-292
18.Akman T,Guven M,Aras A B,Ozkan A,Sen H M,Okuyucu A,Kalkan Y,Sehitoglu I,Silan C,Cosar M.The neuroprotective effect of glycyrrhizic acid on an experimental model of focal cerebral ischemia in rats.Inflammation,2015,38(4):1581-1588
19.Puyal J,Ginet V,Clarke P G.Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage:a challenge for neuroprotection.Progress in Neurobiology,2013,105:24-48
20.Ahmad A S,Shah Z A,DoréS.Protective role of arginase II in cerebral ischemia and excitotoxicity.Journal of Neurology and Neuroscience,2016,7(2):88-93
21.Erd?S,Michler A,Wolff J R.GABA accelerates excitotoxic cell death in cortical cultures:protection by blockers of GABA-gated chloride channels.Brain Research,1991,542(2):254-258
22.Monnerie H,Le Roux P D.Glutamate alteration of glutamic acid decarboxylase(GAD)in GABAergic neurons:the role of cysteine proteases.Experimental Neurology,2008,213(1):145-153
23.Loh K P,Huang S H,Tan B K H,Zhu Y Z.Cerebral protection of purified Herba Leonuri extract on middle cerebral artery occluded rats.Journal of Ethnopharmacology,2009,125(2):337-343
24.Wang Z,Zhang P L,Ju Y.Effect of leonurine on the activity of creatine kinase.Journal of Asian Natural Products Research,2004,6(4):281-287
25.Qi J,Hong Z Y,Xin H,Zhu Y Z.Neuroprotective effects of leonurine on ischemia/reperfusion-induced mitochondrial dysfunctions in rat cerebral cortex.Biological&Pharmaceutical Bulletin,2010,33(12):1958-1964
26.Liu C,Yin H,Gao J,Xu X,Zhang T,Yang Z.Leonurine ameliorates cognitive dysfunction via antagonizing excitotoxic glutamate insults and inhibiting autophagy.Phytomedicine,2016,23(13):1638-1646
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