Kai Xin San ameliorates scopolamine-induced cognitive dysfunction
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摘要
Kai Xin San(KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups(which received physiological saline), the doses of KXS(0.7, 1.4 and 2.8 g/kg per day) and donepezil(3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following.(1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze.(2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze.(3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies.(4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus.(5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxidase, and reduced the level and activity of acetyl cholinesterase, reactive oxygen species, and malondialdehyde through acting on the cholinergic system and reducing oxidative stress damage. These results indicate that KXS plays a neuroprotective role and improves cognitive function through reducing apoptosis and oxidative stress, and regulating synapse-associated protein and cholinergic neurotransmitters.
Kai Xin San(KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups(which received physiological saline), the doses of KXS(0.7, 1.4 and 2.8 g/kg per day) and donepezil(3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following.(1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze.(2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze.(3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies.(4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus.(5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxidase, and reduced the level and activity of acetyl cholinesterase, reactive oxygen species, and malondialdehyde through acting on the cholinergic system and reducing oxidative stress damage. These results indicate that KXS plays a neuroprotective role and improves cognitive function through reducing apoptosis and oxidative stress, and regulating synapse-associated protein and cholinergic neurotransmitters.
Kai Xin San(KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups(which received physiological saline), the doses of KXS(0.7, 1.4 and 2.8 g/kg per day) and donepezil(3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following.(1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze.(2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze.(3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies.(4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus.(5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxidase, and reduced the level and activity of acetyl cholinesterase, reactive oxygen species, and malondialdehyde through acting on the cholinergic system and reducing oxidative stress damage. These results indicate that KXS plays a neuroprotective role and improves cognitive function through reducing apoptosis and oxidative stress, and regulating synapse-associated protein and cholinergic neurotransmitters.
引文
Aliev G,Priyadarshini M,Reddy VP,Grieg NH,Kaminsky Y,Cacabelos R,Ashraf GM,Jabir NR,Kamal MA,Nikolenko VN,Zamyatnin AA,Jr.,Benberin VV,Bachurin SO(2014)Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease.Curr Med Chem 21:2208-2217.
Bayer AJ,Bullock R,Jones RW,Wilkinson D,Paterson KR,Jenkins L,Millais SB,Donoghue S(2005)Evaluation of the safety and immunogenicity of synthetic Abeta42(AN1792)in patients with AD.Neurology 64:94.
Beatty WW,Butters N,Janowsky DS(1986)Patterns of memory failure after scopolamine treatment:Implications for cholinergic hypotheses of dementia.Behav Neural Biol 45:196-211.
Boyle PA,Buchman AS,Wilson RS,Kelly JF,Bennett DA(2010)The APOE epsilon4 allele is associated with incident mild cognitive impairment among community-dwelling older persons.Neuroepidemiology 34:43-49.
Brandeis R,Brandys Y,Yehuda S(1989)The use of the Morris Water Maze in the study of memory and learning.Int J Neurosci 48:29-69.
Budzynska B,Boguszewska-Czubara A,Kruk-Slomka M,Skalicka-Wozniak K,Michalak A,Musik I,Biala G(2015)Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice.Psychopharmacology 232:931-942.
Cao Y,Hu Y,Liu P,Zhao HX,Zhou XJ,Wei YM(2012)Effects of a Chinese traditional formula kai xin san(kxs)on chronic fatigue syndrome mice induced by forced wheel running.J Ethnopharmacol 139:19-25.
Chen W,Cheng X,Chen J,Yi X,Nie D,Sun X,Qin J,Tian M,Jin G,Zhang X(2014)Lycium barbarum polysaccharides prevent memory and neurogenesis impairments in scopolamine-treated rats.PLoSOne 9:e88076.
Dang H,Sun L,Liu X,Peng B,Wang Q,Jia W,Chen Y,Pan A,Xiao P(2009)Preventive action of Kai Xin San aqueous extract on depressive-like symptoms and cognition deficit induced by chronic mild stress.Exp Biol Med 234:785-793.
Di YQ,Sang XX,Fang F(2017)Effects of Kaixin Powder on LTP in vivo and expression of PSD-95 in APP/PSl transgenic mice.Zhong Cheng Yao 471-475.
Dong L,May BH,Feng M,Hyde AJ,Tan HY,Guo X,Zhang AL,Lu C,Xue CC(2016a)Chinese herbal medicine for mild cognitive impairment:a systematic review and meta-analysis of cognitive outcomes.Phytother Res 30:1592-1604.
Dong XZ,Wang DX,Yu BY,Liu P,Hu Y(2016b)Kai-Xin-San,a traditional Chinese medicine formulation,exerts antidepressive and neuroprotective effects by promoting pCREB upstream pathways.Exp Ther Med 12:3308-3314.
Feldman HH et al.(2007)Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment:the InD-DEx study.Lancet Neurol 6:501-512.
Goldsmith KC,Gross M,Peirce S,Luyindula D,Liu X,Vu A,Sliozberg M,Guo R,Zhao H,Reynolds CP,Hogarty MD(2012)Mitochondrial Bcl-2 family dynamics define therapy response and resistance in neuroblastoma.Cancer Res 72:2565-2577.
Hescham S,Temel Y,Casacacarreira J,Arslantas K,Yakkioui Y,Blokland A,Jahanshahi A(2014)A neuroanatomical analysis of the effects of a memory impairing dose of scopolamine in the rat brain using cytochrome c oxidase as principle marker.J Chem Neuroanat 59-60:1-7.
Himeno E,Ohyagi Y,Ma L,Nakamura N,Miyoshi K,Sakae N,Motomura K,Soejima N,Yamasaki R,Hashimoto T,Tabira T,LaFerla FM,Kira J(2011)Apomorphine treatment in Alzheimer mice promoting amyloid-beta degradation.Annals Neurol 69:248-256.
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Holtzman DM(2008)Alzheimer’s disease:moving towards a vaccine.Nature 454:418-420.
Hu Y,Cao Y,Liu M,Liu P,Cui H,Dai-Hong G(2013a)Behavioral and biochemical effects of a formulation of the traditional Chinese medicine,Kai-Xin-San,in fatigued rats.Exp Ther Med 6:973-976.
Hu Y,Liu P,Guo DH,Rahman K,Wang DX,Chen ML,Xie TT(2010)Behavioral and biochemical effects of Kaixin-San,a traditional Chinese medicinal empirical formula.Drug Develop Res 69:267-271.
Hu Y,Liu M,Liu P,Yan JJ,Liu MY,Zhang GQ,Zhou XJ,Yu BY(2013b)Effect of kai xin san on learning and memory in a rat model of paradoxical sleep deprivation.J Med Food 16:280-287.
Ishola IO,Tota S,Adeyemi OO,Agbaje EO,Narender T,Shukla R(2013)Protective effect of Cnestis ferruginea and its active constituent on scopolamine-induced memory impairment in mice:a behavioral and biochemical study.Pharm Biol 51:825-835.
Jahanshahi M,Nickmahzar EG,Babakordi F(2013)Effect of Gingko biloba extract on scopolamine-induced apoptosis in the hippocampus of rats.Anat Sci Int 88:217-222.
Ji RF,Niu JZ,Xu AQ(2006)Determining the effects of Chinese medicine on Amnesia and/or dementias through data Mining.Zhongri Youhao Yiyuan Xuebao 20:337-340.
Kilimann I,Hausner L,Fellgiebel A,Filippi M,Wurdemann TJ,Heinsen H,Teipel SJ(2017)Parallel atrophy of cortex and basal forebrain cholinergic system in mild cognitive impairment.Cereb Cortex 27:1841-1848.
Kim DH,Jeon SJ,Son KH,Jung JW,Lee S,Yoon BH,Lee JJ,Cho YW,Cheong JH,Ko KH,Ryu JH(2007)The ameliorating effect of oroxylin A on scopolamine-induced memory impairment in mice.Neurobiol Learn Mem 87:536-546.
Kim DH,Park SJ,Kim JM,Jeon SJ,Kim DH,Cho YW,Son KH,Lee HJ,Moon JH,Cheong JH,Ko KH,Ryu JH(2011)Cognitive dysfunctions induced by a cholinergic blockade and Abeta 25-35 peptide are attenuated by salvianolic acid B.Neuropharmacology 61:1432-1440.
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Lian W,Fang J,Xu L,Zhou W,Kang,Xiong W,Jia H,Liu AL,Du GH(2017)DL0410 Ameliorates memory and cognitive impairments induced by scopolamine via increasing cholinergic neurotransmission in mice.Molecules 22:410.
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Beatty WW,Butters N,Janowsky DS(1986)Patterns of memory failure after scopolamine treatment:Implications for cholinergic hypotheses of dementia.Behav Neural Biol 45:196-211.
Boyle PA,Buchman AS,Wilson RS,Kelly JF,Bennett DA(2010)The APOE epsilon4 allele is associated with incident mild cognitive impairment among community-dwelling older persons.Neuroepidemiology 34:43-49.
Brandeis R,Brandys Y,Yehuda S(1989)The use of the Morris Water Maze in the study of memory and learning.Int J Neurosci 48:29-69.
Budzynska B,Boguszewska-Czubara A,Kruk-Slomka M,Skalicka-Wozniak K,Michalak A,Musik I,Biala G(2015)Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice.Psychopharmacology 232:931-942.
Cao Y,Hu Y,Liu P,Zhao HX,Zhou XJ,Wei YM(2012)Effects of a Chinese traditional formula kai xin san(kxs)on chronic fatigue syndrome mice induced by forced wheel running.J Ethnopharmacol 139:19-25.
Chen W,Cheng X,Chen J,Yi X,Nie D,Sun X,Qin J,Tian M,Jin G,Zhang X(2014)Lycium barbarum polysaccharides prevent memory and neurogenesis impairments in scopolamine-treated rats.PLoSOne 9:e88076.
Dang H,Sun L,Liu X,Peng B,Wang Q,Jia W,Chen Y,Pan A,Xiao P(2009)Preventive action of Kai Xin San aqueous extract on depressive-like symptoms and cognition deficit induced by chronic mild stress.Exp Biol Med 234:785-793.
Di YQ,Sang XX,Fang F(2017)Effects of Kaixin Powder on LTP in vivo and expression of PSD-95 in APP/PSl transgenic mice.Zhong Cheng Yao 471-475.
Dong L,May BH,Feng M,Hyde AJ,Tan HY,Guo X,Zhang AL,Lu C,Xue CC(2016a)Chinese herbal medicine for mild cognitive impairment:a systematic review and meta-analysis of cognitive outcomes.Phytother Res 30:1592-1604.
Dong XZ,Wang DX,Yu BY,Liu P,Hu Y(2016b)Kai-Xin-San,a traditional Chinese medicine formulation,exerts antidepressive and neuroprotective effects by promoting pCREB upstream pathways.Exp Ther Med 12:3308-3314.
Feldman HH et al.(2007)Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment:the InD-DEx study.Lancet Neurol 6:501-512.
Goldsmith KC,Gross M,Peirce S,Luyindula D,Liu X,Vu A,Sliozberg M,Guo R,Zhao H,Reynolds CP,Hogarty MD(2012)Mitochondrial Bcl-2 family dynamics define therapy response and resistance in neuroblastoma.Cancer Res 72:2565-2577.
Hescham S,Temel Y,Casacacarreira J,Arslantas K,Yakkioui Y,Blokland A,Jahanshahi A(2014)A neuroanatomical analysis of the effects of a memory impairing dose of scopolamine in the rat brain using cytochrome c oxidase as principle marker.J Chem Neuroanat 59-60:1-7.
Himeno E,Ohyagi Y,Ma L,Nakamura N,Miyoshi K,Sakae N,Motomura K,Soejima N,Yamasaki R,Hashimoto T,Tabira T,LaFerla FM,Kira J(2011)Apomorphine treatment in Alzheimer mice promoting amyloid-beta degradation.Annals Neurol 69:248-256.
Holmes C,Boche D,Wilkinson D,Yadegarfar G,Hopkins V,Bayer A,Jones RW,Bullock R,Love S,Neal JW,Zotova E,Nicoll JA(2008)Long-term effects of Abeta42 immunisation in Alzheimer’s disease:follow-up of a randomised,placebo-controlled phase I trial.Lancet372:216-223.
Holtzman DM(2008)Alzheimer’s disease:moving towards a vaccine.Nature 454:418-420.
Hu Y,Cao Y,Liu M,Liu P,Cui H,Dai-Hong G(2013a)Behavioral and biochemical effects of a formulation of the traditional Chinese medicine,Kai-Xin-San,in fatigued rats.Exp Ther Med 6:973-976.
Hu Y,Liu P,Guo DH,Rahman K,Wang DX,Chen ML,Xie TT(2010)Behavioral and biochemical effects of Kaixin-San,a traditional Chinese medicinal empirical formula.Drug Develop Res 69:267-271.
Hu Y,Liu M,Liu P,Yan JJ,Liu MY,Zhang GQ,Zhou XJ,Yu BY(2013b)Effect of kai xin san on learning and memory in a rat model of paradoxical sleep deprivation.J Med Food 16:280-287.
Ishola IO,Tota S,Adeyemi OO,Agbaje EO,Narender T,Shukla R(2013)Protective effect of Cnestis ferruginea and its active constituent on scopolamine-induced memory impairment in mice:a behavioral and biochemical study.Pharm Biol 51:825-835.
Jahanshahi M,Nickmahzar EG,Babakordi F(2013)Effect of Gingko biloba extract on scopolamine-induced apoptosis in the hippocampus of rats.Anat Sci Int 88:217-222.
Ji RF,Niu JZ,Xu AQ(2006)Determining the effects of Chinese medicine on Amnesia and/or dementias through data Mining.Zhongri Youhao Yiyuan Xuebao 20:337-340.
Kilimann I,Hausner L,Fellgiebel A,Filippi M,Wurdemann TJ,Heinsen H,Teipel SJ(2017)Parallel atrophy of cortex and basal forebrain cholinergic system in mild cognitive impairment.Cereb Cortex 27:1841-1848.
Kim DH,Jeon SJ,Son KH,Jung JW,Lee S,Yoon BH,Lee JJ,Cho YW,Cheong JH,Ko KH,Ryu JH(2007)The ameliorating effect of oroxylin A on scopolamine-induced memory impairment in mice.Neurobiol Learn Mem 87:536-546.
Kim DH,Park SJ,Kim JM,Jeon SJ,Kim DH,Cho YW,Son KH,Lee HJ,Moon JH,Cheong JH,Ko KH,Ryu JH(2011)Cognitive dysfunctions induced by a cholinergic blockade and Abeta 25-35 peptide are attenuated by salvianolic acid B.Neuropharmacology 61:1432-1440.
Kopelman MD,Corn TH(1988)Cholinergic‘blockade’as a model for cholinergic depletion.A comparison of the memory deficits with those of Alzheimer-type dementia and the alcoholic Korsakoff syndrome.Brain 111:1079-1110.
Kulshreshtha A,Piplani P(2016)Ameliorative effects of amide derivatives of 1,3,4-thiadiazoles on scopolamine induced cognitive dysfunction.Eur J Med Chem 122:557-573.
Li ZL,Dong XZ,Wang DX,Dong RH,Guo TT,Sun Y,Liu P(2014)Effect of oligosaccharide esters and polygalaxanthone III from Polygala tenuifolia willd towards cytochrome P450.Zhongguo Zhongyao Zazhi 39:4459.
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