Xiao-Xu-Ming decoction extract regulates differentially expressed proteins in the hippocampus after chronic cerebral hypoperfusion
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摘要
Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2 a, Ptpn1, Ppm1 e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MTND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.
Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2 a, Ptpn1, Ppm1 e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MTND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.
Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2 a, Ptpn1, Ppm1 e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MTND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.
引文
Aebersold R,Mann M(2003)Mass spectrometry-based proteomics.Nature 422:198-207.
Altelaar AF,Munoz J,Heck AJ(2013)Next-generation proteomics:towards an integrative view of proteome dynamics.Nat Rev Genet 14:35-48.
Ang CS,Baker MS,Nice EC(2017)Mass spectrometry-based analysis for the discovery and validation of potential colorectal cancer stool biomarkers.Methods Enzymol 586:247-274.
Battistin L,Cagnin A(2010)Vascular cognitive disorder.A biological and clinical overview.Neurochem Res 35:1933-1938.
Buzsáki G,Moser EI(2013)Memory,navigation and theta rhythm in the hippocampal-entorhinal system.Nat Neurosci 16:130-138.
Chen DP,Hou SH,Guo Y,Hu ZZ,Hu XH,Chen YG,Chen MS(2018)Human placenta-derived mesenchymal stem cell transplantation provides neuroprotection against cerebral infarction in rats.Zhongguo Zuzhi Gongcheng Yanjiu 22:65-69.
DanielisováV,Gottlieb M,NémethováM,Krav?ukováP,DomorákováI,MechírováE,Burda J(2009)Bradykinin postconditioning protects pyramidal ca1 neurons against delayed neuronal death in rat hippocampus.Cell Mol Neurobiol 29:871-878.
Du K,Wu C,Ding C,Zhao S,Qin H,Zhang J(2009)Simultaneous LC-MS Analysis and of wogonin and oroxylin a in rat plasma,and pharmacokinetic studies after administration of the active fraction from Xiao-Xu-Ming Decoction.Chromatographia 69:1259.
Efremov RG,Baradaran R,Sazanov LA(2010)The architecture of respiratory complex I.Nature 465:441-445.
Gorman GS,Blakely EL,Hornig-Do HT,Tuppen HA,Greaves LC,He L,Baker A,Falkous G,Newman J,Trenell MI,Lecky B,Petty RK,Turnbull DM,McFarland R,Taylor RW(2015)Novel MTND1 mutations cause isolated exercise intolerance,complex I deficiency and increased assembly factor expression.Clin Sci(Lond)128:895-904.
He XL,Wang YH,Bi MG,Du GH(2012)Chrysin improves cognitive deficits and brain damage induced by chronic cerebral hypoperfusion in rats.Eur J Pharmacol 680:41-48.
Hermann DM,Buga AM,Popa-Wagner A(2015)Neurovascular remodeling in the aged ischemic brain.J Neural Transm(Vienna)122 Suppl1:S25-33.
Ihara M,Taguchi A,Maki T,Washida K,Tomimoto H(2014)A mouse model of chronic cerebral hypoperfusion characterizing features of vascular cognitive impairment.Methods Mol Biol 1135:95-102.
Jing Z,Shi C,Zhu L,Xiang Y,Chen P,Xiong Z,Li W,Ruan Y,Huang L(2015a)Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment.J Cereb Blood Flow Metab 35:1249-1259.
Jing Z,Shi C,Zhu L,Xiang Y,Chen P,Xiong Z,Li W,Ruan Y,Huang La(2015b)Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment.J Cereb Blood Flow Metab 35:1249-1259.
Keilhauer EC,Hein MY,Mann M(2015)Accurate protein complex retrieval by affinity enrichment mass spectrometry(AE-MS)rather than affinity purification mass spectrometry(AP-MS).Mol Cell Proteomics14:120-135.
Lan R,Xiang J,Wang GH,Li WW,Zhang W,Xu LL,Cai DF(2013)XiaoXu-Ming Decoction protects against blood-brain barrier disruption and neurological injury induced by cerebral ischemia and reperfusion in rats.Evid Based Complement Alternat Med 2013:629782.
Lan R,Zhang Y,Xiang J,Zhang W,Wang GH,Li WW,Xu LL,Cai DF(2014)Xiao-Xu-Ming decoction preserves mitochondrial integrity and reduces apoptosis after focal cerebral ischemia and reperfusion via the mitochondrial p53 pathway.J Ethnopharmacol 151:307-316.
Lim SC,HroudováJ,Van Bergen NJ,Lopez Sanchez MI,Trounce IA,McKenzie M(2016)Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly.FASEB J 30:2236-2248.
Liu HX,Zhang JJ,Zheng P,Zhang Y(2005)Altered expression of MAP-2,GAP-43,and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment.Brain Res Mol Brain Res 139:169-177.
Luber CA,Cox J,Lauterbach H,Fancke B,Selbach M,Tschopp J,Akira S,Wiegand M,Hochrein H,O’Keeffe M,Mann M(2010)Quantitative proteomics reveals subset-specific viral recognition in dendritic cells.Immunity 32:279-289.
Popa-Wagner A,Buga AM,Popescu B,Muresanu D(2015)Vascular cognitive impairment,dementia,aging and energy demand.A vicious cycle.J Neural Transm(Vienna)122 Suppl 1:S47-54.
Sandu RE,Buga AM,Uzoni A,Petcu EB,Popa-Wagner A(2015)Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology.Neural Regen Res 10:1349-1355.
Seo HG,Kim DY,Park HW,Lee SU,Park SH(2010)Early motor balance and coordination training increased synaptophysin in subcortical regions of the ischemic rat brain.J Korean Med Sci 25:1638-1645.
Sugawara Y,Kikuchi T,Ueda T,Nishizaki M,Nakata S,Mochizuki T,Ikezoe J(2002)Usefulness of brain SPECT to evaluate brain tolerance and hemodynamic changes during temporary balloon occlusion test and after permanent carotid occlusion.J Nucl Med 43:1616-1623.
Tanaka K,Wada-Tanaka N,Miyazaki I,Nomura M,Ogawa N(2002)Chronic cerebral hypoperfusion induces striatal alterations due to the transient increase of NO production and the depression of glutathione content.Neurochem Res 27:331-336.
Traditional Chinese Medicine Terminology Committee(2005)Basic Terms of Traditional Chinese Medicine.Beijing:Science Press.
Tsai TH,Song E,Zhu R,Di Poto C,Wang M,Luo Y,Varghese RS,Tadesse MG,Ziada DH,Desai CS,Shetty K,Mechref Y,Ressom HW(2015)LC-MS/MS-based serum proteomics for identification of candidate biomarkers for hepatocellular carcinoma.Proteomics 15:2369-2381.
Venkat P,Chopp M,Chen J(2015)Models and mechanisms of vascular dementia.Exp Neurol 272:97-108.
Walther TC,Mann M(2010)Mass spectrometry-based proteomics in cell biology.J Cell Biol 190:491-500.
Wang C,Jia Z,Wang Z,Hu T,Qin H,Du G,Wu C,Zhang J(2016)Pharmacokinetics of 21 active components in focal cerebral ischemic rats after oral administration of the active fraction of Xiao-Xu-Ming decoction.J Pharm Biomed Anal 122:110-117.
Wang CH,Wu CS,Qin HL,Zhang JL(2014)Rapid discovery and identification of 68 compounds in the active fraction from Xiao-Xu-Ming decoction(XXMD)by HPLC-HRMS and MTSF technique.Chin Chem Lett 25:1648-1652.
Wang Y,Qin H,He X,Du G(2011)Activity evaluation of components and preparation of effective components group of xiaoxuming decoction for anti-cerebral ischemic.Zhongguo Zhong Yao Za Zhi 36:2140-2144.
Wang YH,He XL,Yang HG,Qin HL,Du GH(2012a)Effects of the active components of Chinese herbal medicine Xiaoxuming Decoction on memory behavior and brain injury in rats with chronic cerebral ischemia.Zhong Xi Yi Jie He Xue Bao 10:91-99.
Wang YH,Hem XL,Yang HG,Qin HL,Du GH(2012b)Effects of the effective components group of Xiaoxuming Decoction on MCAO rats.Zhongguo Yaoxue Zazhi 47:194-198.
Wang YH,He XL,Li XX,Qin HL,Du GH(2012c)Effects of the effective component group of Chinese herbal medicine Xiaoxuming Decoction on brain mitochondria in rats with chronic cerebral ischemia.Zhong Xi Yi Jie He Xue Bao 10:569-576.
Xu G,Li Z,Wang L,Chen F,Chi Z,Gu M,Li S,Wu D,Miao J,Zhang Y,Hao L,Fan Y(2017)Label-free quantitative proteomics reveals differentially expressed proteins in high risk childhood acute lymphoblastic leukemia.J Proteomics 150:1-8.
Yan C,Zhang J,Wang S,Xue G,Hou Y(2013)Neuroprotective effects of rutaecarpine on cerebral ischemia reperfusion injury.Neural Regen Res 8:2030-2038.
Yonemori F,Yamaguchi T,Yamada H,Tamura A(1998)Evaluation of a motor deficit after chronic focal cerebral ischemia in rats.J Cereb Blood Flow Metab 18:1099-1106.
Zhang XA(2016)Cortical mechanism underlying aerobic exercise promoting cognitive function of vascular dementia rats:study protocol for a randomized controlled trial.Zhongguo Zuzhi Gongcheng Yanjiu20:6943-6949.
Zhong L,Zhou J,Chen X,Lou Y,Liu D,Zou X,Yang B,Yin Y,Pan Y(2016)Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells.Sci Rep 6:22635.
Zhu JD,Wang JJ,Zhang XH,Yu Y,Kang ZS(2018)Panax ginseng extract attenuates neuronal injury and cognitive deficits in rats with vascular dementia induced by chronic cerebral hypoperfusion.Neural Regen Res 13:664-672.
Zuloaga KL,Zhang W,Yeiser LA,Stewart B,Kukino A,Nie X,Roese NE,Grafe MR,Pike MM,Raber J,Alkayed NJ(2015)Neurobehavioral and imaging correlates of hippocampal atrophy in a mouse model of vascular cognitive impairment.Transl Stroke Res 6:390-398.
Altelaar AF,Munoz J,Heck AJ(2013)Next-generation proteomics:towards an integrative view of proteome dynamics.Nat Rev Genet 14:35-48.
Ang CS,Baker MS,Nice EC(2017)Mass spectrometry-based analysis for the discovery and validation of potential colorectal cancer stool biomarkers.Methods Enzymol 586:247-274.
Battistin L,Cagnin A(2010)Vascular cognitive disorder.A biological and clinical overview.Neurochem Res 35:1933-1938.
Buzsáki G,Moser EI(2013)Memory,navigation and theta rhythm in the hippocampal-entorhinal system.Nat Neurosci 16:130-138.
Chen DP,Hou SH,Guo Y,Hu ZZ,Hu XH,Chen YG,Chen MS(2018)Human placenta-derived mesenchymal stem cell transplantation provides neuroprotection against cerebral infarction in rats.Zhongguo Zuzhi Gongcheng Yanjiu 22:65-69.
DanielisováV,Gottlieb M,NémethováM,Krav?ukováP,DomorákováI,MechírováE,Burda J(2009)Bradykinin postconditioning protects pyramidal ca1 neurons against delayed neuronal death in rat hippocampus.Cell Mol Neurobiol 29:871-878.
Du K,Wu C,Ding C,Zhao S,Qin H,Zhang J(2009)Simultaneous LC-MS Analysis and of wogonin and oroxylin a in rat plasma,and pharmacokinetic studies after administration of the active fraction from Xiao-Xu-Ming Decoction.Chromatographia 69:1259.
Efremov RG,Baradaran R,Sazanov LA(2010)The architecture of respiratory complex I.Nature 465:441-445.
Gorman GS,Blakely EL,Hornig-Do HT,Tuppen HA,Greaves LC,He L,Baker A,Falkous G,Newman J,Trenell MI,Lecky B,Petty RK,Turnbull DM,McFarland R,Taylor RW(2015)Novel MTND1 mutations cause isolated exercise intolerance,complex I deficiency and increased assembly factor expression.Clin Sci(Lond)128:895-904.
He XL,Wang YH,Bi MG,Du GH(2012)Chrysin improves cognitive deficits and brain damage induced by chronic cerebral hypoperfusion in rats.Eur J Pharmacol 680:41-48.
Hermann DM,Buga AM,Popa-Wagner A(2015)Neurovascular remodeling in the aged ischemic brain.J Neural Transm(Vienna)122 Suppl1:S25-33.
Ihara M,Taguchi A,Maki T,Washida K,Tomimoto H(2014)A mouse model of chronic cerebral hypoperfusion characterizing features of vascular cognitive impairment.Methods Mol Biol 1135:95-102.
Jing Z,Shi C,Zhu L,Xiang Y,Chen P,Xiong Z,Li W,Ruan Y,Huang L(2015a)Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment.J Cereb Blood Flow Metab 35:1249-1259.
Jing Z,Shi C,Zhu L,Xiang Y,Chen P,Xiong Z,Li W,Ruan Y,Huang La(2015b)Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment.J Cereb Blood Flow Metab 35:1249-1259.
Keilhauer EC,Hein MY,Mann M(2015)Accurate protein complex retrieval by affinity enrichment mass spectrometry(AE-MS)rather than affinity purification mass spectrometry(AP-MS).Mol Cell Proteomics14:120-135.
Lan R,Xiang J,Wang GH,Li WW,Zhang W,Xu LL,Cai DF(2013)XiaoXu-Ming Decoction protects against blood-brain barrier disruption and neurological injury induced by cerebral ischemia and reperfusion in rats.Evid Based Complement Alternat Med 2013:629782.
Lan R,Zhang Y,Xiang J,Zhang W,Wang GH,Li WW,Xu LL,Cai DF(2014)Xiao-Xu-Ming decoction preserves mitochondrial integrity and reduces apoptosis after focal cerebral ischemia and reperfusion via the mitochondrial p53 pathway.J Ethnopharmacol 151:307-316.
Lim SC,HroudováJ,Van Bergen NJ,Lopez Sanchez MI,Trounce IA,McKenzie M(2016)Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly.FASEB J 30:2236-2248.
Liu HX,Zhang JJ,Zheng P,Zhang Y(2005)Altered expression of MAP-2,GAP-43,and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment.Brain Res Mol Brain Res 139:169-177.
Luber CA,Cox J,Lauterbach H,Fancke B,Selbach M,Tschopp J,Akira S,Wiegand M,Hochrein H,O’Keeffe M,Mann M(2010)Quantitative proteomics reveals subset-specific viral recognition in dendritic cells.Immunity 32:279-289.
Popa-Wagner A,Buga AM,Popescu B,Muresanu D(2015)Vascular cognitive impairment,dementia,aging and energy demand.A vicious cycle.J Neural Transm(Vienna)122 Suppl 1:S47-54.
Sandu RE,Buga AM,Uzoni A,Petcu EB,Popa-Wagner A(2015)Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology.Neural Regen Res 10:1349-1355.
Seo HG,Kim DY,Park HW,Lee SU,Park SH(2010)Early motor balance and coordination training increased synaptophysin in subcortical regions of the ischemic rat brain.J Korean Med Sci 25:1638-1645.
Sugawara Y,Kikuchi T,Ueda T,Nishizaki M,Nakata S,Mochizuki T,Ikezoe J(2002)Usefulness of brain SPECT to evaluate brain tolerance and hemodynamic changes during temporary balloon occlusion test and after permanent carotid occlusion.J Nucl Med 43:1616-1623.
Tanaka K,Wada-Tanaka N,Miyazaki I,Nomura M,Ogawa N(2002)Chronic cerebral hypoperfusion induces striatal alterations due to the transient increase of NO production and the depression of glutathione content.Neurochem Res 27:331-336.
Traditional Chinese Medicine Terminology Committee(2005)Basic Terms of Traditional Chinese Medicine.Beijing:Science Press.
Tsai TH,Song E,Zhu R,Di Poto C,Wang M,Luo Y,Varghese RS,Tadesse MG,Ziada DH,Desai CS,Shetty K,Mechref Y,Ressom HW(2015)LC-MS/MS-based serum proteomics for identification of candidate biomarkers for hepatocellular carcinoma.Proteomics 15:2369-2381.
Venkat P,Chopp M,Chen J(2015)Models and mechanisms of vascular dementia.Exp Neurol 272:97-108.
Walther TC,Mann M(2010)Mass spectrometry-based proteomics in cell biology.J Cell Biol 190:491-500.
Wang C,Jia Z,Wang Z,Hu T,Qin H,Du G,Wu C,Zhang J(2016)Pharmacokinetics of 21 active components in focal cerebral ischemic rats after oral administration of the active fraction of Xiao-Xu-Ming decoction.J Pharm Biomed Anal 122:110-117.
Wang CH,Wu CS,Qin HL,Zhang JL(2014)Rapid discovery and identification of 68 compounds in the active fraction from Xiao-Xu-Ming decoction(XXMD)by HPLC-HRMS and MTSF technique.Chin Chem Lett 25:1648-1652.
Wang Y,Qin H,He X,Du G(2011)Activity evaluation of components and preparation of effective components group of xiaoxuming decoction for anti-cerebral ischemic.Zhongguo Zhong Yao Za Zhi 36:2140-2144.
Wang YH,He XL,Yang HG,Qin HL,Du GH(2012a)Effects of the active components of Chinese herbal medicine Xiaoxuming Decoction on memory behavior and brain injury in rats with chronic cerebral ischemia.Zhong Xi Yi Jie He Xue Bao 10:91-99.
Wang YH,Hem XL,Yang HG,Qin HL,Du GH(2012b)Effects of the effective components group of Xiaoxuming Decoction on MCAO rats.Zhongguo Yaoxue Zazhi 47:194-198.
Wang YH,He XL,Li XX,Qin HL,Du GH(2012c)Effects of the effective component group of Chinese herbal medicine Xiaoxuming Decoction on brain mitochondria in rats with chronic cerebral ischemia.Zhong Xi Yi Jie He Xue Bao 10:569-576.
Xu G,Li Z,Wang L,Chen F,Chi Z,Gu M,Li S,Wu D,Miao J,Zhang Y,Hao L,Fan Y(2017)Label-free quantitative proteomics reveals differentially expressed proteins in high risk childhood acute lymphoblastic leukemia.J Proteomics 150:1-8.
Yan C,Zhang J,Wang S,Xue G,Hou Y(2013)Neuroprotective effects of rutaecarpine on cerebral ischemia reperfusion injury.Neural Regen Res 8:2030-2038.
Yonemori F,Yamaguchi T,Yamada H,Tamura A(1998)Evaluation of a motor deficit after chronic focal cerebral ischemia in rats.J Cereb Blood Flow Metab 18:1099-1106.
Zhang XA(2016)Cortical mechanism underlying aerobic exercise promoting cognitive function of vascular dementia rats:study protocol for a randomized controlled trial.Zhongguo Zuzhi Gongcheng Yanjiu20:6943-6949.
Zhong L,Zhou J,Chen X,Lou Y,Liu D,Zou X,Yang B,Yin Y,Pan Y(2016)Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells.Sci Rep 6:22635.
Zhu JD,Wang JJ,Zhang XH,Yu Y,Kang ZS(2018)Panax ginseng extract attenuates neuronal injury and cognitive deficits in rats with vascular dementia induced by chronic cerebral hypoperfusion.Neural Regen Res 13:664-672.
Zuloaga KL,Zhang W,Yeiser LA,Stewart B,Kukino A,Nie X,Roese NE,Grafe MR,Pike MM,Raber J,Alkayed NJ(2015)Neurobehavioral and imaging correlates of hippocampal atrophy in a mouse model of vascular cognitive impairment.Transl Stroke Res 6:390-398.
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