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scopolamine causes delirium-like brain network dysfunction and reversible cognitive impairment without neuronal loss

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Zoological Research 2023年第4期44卷 712-724页

作者： Qing Wang Xiang Zhang Yu-Jie Guo Ya-Yan Pang Jun-Jie Li Yan-Li Zhao Jun-Fen Wei Bai-Ting Zhu Jing-Xiang Tang Yang-Yang Jiang Jie Meng Ji-Rong Yue Peng Lei Department of Geriatrics and State Key Laboratory of Biotherapy National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan 610041China Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China

Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later ***,given its inherent complexity,few animal models of delirium have been established and the mechanism underlying the onset of delirium remains ***,we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors,including anesthesia with surgery(AS),systemic inflammation,and neurotransmission *** found that both bacterial lipopolysaccharide(LPS)and cholinergic receptor antagonist scopolamine(Scop)induction reduced neuronal activities in the delirium-related brain network,with the latter presenting a similar pattern of reduction as found in delirium ***,Scop injection resulted in reversible cognitive impairment with hyperactive *** loss of cholinergic neurons was found with treatment,but hippocampal synaptic functions were *** findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.

关键词： Delirium scopolamine Cholinergic neuron Neuronal activity Brain network

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Kai Xin San ameliorates scopolamine-induced cognitive dysfunction

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Neural Regeneration Research 2019年第5期14卷 794-804页

作者： Yu-Min Xu Xin-Chen Wang Ting-Ting Xu Hong-Ying Li Shang-Yan Hei Na-Chuan Luo Hong Wang Wei Zhao Shu-Huan Fang Yun-Bo Chen Li Guan Yong-Qi Fang Shi-Jie Zhang Qi Wang Wei-Xiong Liang Institute of Clinical Pharmacology Guangzhou University of Chinese Medicine First Affiliated Hospital of Henan University of Chinese Medicine School of Food and Pharmaceutical Engineering Zhaoqing University First Affiliated Hospital of Guangzhou University of Chinese Medicine Department of Neurology The First Affiliated Hospital Guangzhou Medical University Guangdong Provincial Hospital of Chinese Medicine

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, acetylcholi

关键词： Kai Xin San cognitive dysfunction scopolamine hydrobromide neuroprotection oxidative stress synaptic dysfunction apoptosis cholinergic system dysfunction donepezil neural regeneration

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Neuroprotection of N-benzylcinnamide on scopolamine-induced cholinergic dysfunction in human SH-SY5Y neuroblastoma cells

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Neural Regeneration Research 2017年第9期12卷 1492-1498页

作者： Nicha Puangmalai Wipawan Thangnipon Rungtip Soi-ampornkul Nirut Suwanna Patoomratana Tuchinda Saksit Nobsathian Research Center for Neuroscience Institute of Molecular Biosciences Mahidol University Department of Biochemistry Faculty of Medicine Siriraj Hospital Mahidol University Department of Companion Animal Clinical Sciences Faculty of Veterinary Medicine Kasetsart University Department of Chemistry Faculty of Science Mahidol University Nakhon Sawan Campus Mahidol University

Alzheimer＇s disease, a progressive neurodegenerative disease, affects learning and memory resulting from cholinergic dysfunction. scopolamine has been employed to induce Alzheimer＇s disease-like pathology in vivo and in vitro through alteration of cholinergic system. N-benzylcinnamide （PT-3）, purified from Piper submultinerve, has been shown to exhibit neuroprotective properties against amyloid-β-induced neuronal toxicity in rat cortical primary cell culture and to improve spatial learning and memory of aged rats through alleviating oxidative stress. We proposed a hypothesis that PT3 has a neuroprotective effect against scopolamine-induced cholinergic dysfunction. PT-3 （125-200 nM） pretreatment was performed in human neuroblastoma SH-SY5Y cell line following scopolamine induction. PT-3 （125-200 nM） inhibited scopolamine （2 mM）-induced generation of reactive oxygen species, cellular apoptosis, upregutation of ace- tylcholinesterase activity, downregulation of choline acetyltransferase level, and activation of p38 and JNK signalling pathways. These findings revealed the underlying mechanisms of scopolamine-induced Alzheimer＇s disease-like cellular dysfunctions, which provide evidence for developing drugs for the treatment of this de- bilitating disease.

关键词： Alzheimer's disease acetylcholine apoptosis acetylcholinesterase inhibitor oxidative stress N-benzylcinnamide natural product scopolamine neuronal regeneration

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Nacre extract prevents scopolamine-induced memory deficits in rodents

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Asian Pacific Journal of Tropical Medicine 2018年第3期11卷 202-208页

作者： Tatsuya Fuji Tatsurou Inoue Yasushi Hasegawa College of Environmental Technology Muroran Institute of Technology

Objective: To investigate whether the extract from the nacreous layer of pearl oysters(nacre extract) improves impairments in memory caused by scopolamine administration in ***: Nacre extract was prepared from the inner shell layer of pearl oyster. Effects of nacre extract on scopolamine-induced memory impairment were estimated using novel object recognition test, Y-maze test, and Barnes maze test Effect of nacre extract on mRNA expressions which are genes associated with memory in the hippocampus was investigated using semi-quantitative reverse transcription polymerase chain reaction(RT-PCR) ***: Administration of nacre extract led to the protection against scopolamine-induced impairments in object recognition, short-term memory, and spatial memory. Treatment with nacre extract reversed the mRNA expression of brain-derived neurotrophic factor(BDNF) and Homer protein homolog 1(Homer-1 a) in the hippocampus, which decreased with the treatment of scopolamine. Conclusions: These results suggest that nacre extract has attenuating effects on memory impairments induced by scopolamine through the increase in mRNA expression of BDNF and Homer-1 a.

关键词： Nacre extract scopolamine Memory impairment

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Novel insights on acetylcholinesterase inhibition by Convolvulus pluricaulis,scopolamine and their combination in zebrafish

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Natural Products and Bioprospecting 2022年第1期12卷 56-70页

作者： Kalyani Bindu Karunakaran Anand Thiyagaraj Kirankumar Santhakumar Supercomputer Education and Research Centre Indian Institute of Sci-enceBengaluruIndia Department of Genetic Engineering SRM Institute of Science and TechnologyKattankulathur 603203India Zebrafish Genetics Laboratory Department of Genetic EngineeringSRM Institute of Science and TechnologyKattankulathur 603203India

Acetylcholinesterase(AChE)inhibitors increase the retention of acetylcholine(ACh)in *** they allevi-ate cognitive deficits in Alzheimer’s disease,their limited benefits warrant investigations of plant extracts with similar *** studied the anti-AChE activity of Convolvulus pluricaulis(CP)in a zebrafish model of cognitive impair-ment induced by scopolamine(SCOP).CP is a perennial herb with anti-amnesiac and anxiolytic *** contains alkaloid,anthocyanin,coumarin,flavonoid,phytosterol and triterpenoid ***(ISOX)was used as a positive control for AChE ***-treated 168 hpf larvae showed a similar pattern of AChE inhibition(in the myelencephalon and somites)as that of ISOX-treated *** was superior to ISOX as evidenced by the retention of avoidance response behavior in adult *** docking studies indicated that ISOX binds Ser203 of the catalytic triad on the human *** active components of CP-scopoletin and kaempferol-were bound by His447 of the catalytic triad,the anionic subsite of the catalytic center,and the peripheral anionic *** suggested the ability of CP to mediate both competitive and non-competitive modes of ***,SCOP showed AChE inhibition in larvae,possibly mediated via the choline-binding ***+SCOP induced a concentration-dependent increase in AChE inhibition and ACh *** motor responses were observed with ISOX,CP,ISOX+SCOP,and CP+SCOP,indicative of undesirable effects on the peripheral cholinergic *** study proposes the examination of CP,SCOP,and CP+SCOP as potential AChE inhibitors for their ability to modulate cognitive deficits.

关键词： Alzheimer’s disease Acetylcholinesterase Zebrafish Convolvulus pluricaulis scopolamine Isoxazole

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Effects of GBEE on memory impairment induced by scopolamine in mice and activity of AChE in cerebral cortex

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中国药理学与毒理学杂志 2019年第10期 846-847页

作者： LUO Cheng-rong WANG Meng-meng CHEN Jing-ru MAO Lei-lei XU Ai-hua Institute of Translational Medicine Medical Colege Yangzhou University

OBJECTIVE The fruit of Ginkgo biloba *** also known as Ginkgo nuts. Ginkgo has the effect of warming the lung, boosting qi, downbear phlegm, dispersing toxin, kil ing worms and etc, which also recorded in ancient books on tumor treatment. The scientific name of succulent skin is exocarp in Gingko nuts. Research shows that GBEE(Ginkgo biloba exocarp extracts) has anti-tumor,anti-aging and immune promoting activity. As an M receptor blocker, scopolamine can block the excitatory effect of acetylcholine on M receptors, causing learning and memory dysfunction. It can partially simulate some features of the cholinergic system of Alzheimer disease(AD). The learning and memory impairment model of scopolamine is the classic screening model for AD drug research. In this paper, the effects of GBEE on scopolamine induced learning and memory impairment in mice and its mechanism were preliminarily studied. METHODS GBEE was prepared by the patented method(patent: ZL201610916394.4). Infrared Spectroscopy(IR) analysis shows that the proteoglycan in GBEE is ester linkage. The total content of proteoglycan in GBEE was 62.6%-64.8%, which was measured by phenol sulfuric acid method and brilliant blue method. Pre-column derivatization high-performance liquid chromatography(HPLC) detection showed that the proteoglycan in GBEE contains 6 kinds of monosaccharides including mannose, rhamnose, galacturonic acid, glucose, galactose, arabinose and 14 kinds of amino acids including aspartic acid, glutamic acid, glycine,serine, threonine, alanine, proline, valine, methionine,isoleucine, leucine, phenylalanine, tryptophan and lysine.60 ICR mice, half male and half female, 6-8 weeks old and weight(18-22) g, were randomly divided into six groups: blank control group(normal saline), model group(normal saline), positive drug group( donepezi 1.25 mg·kg-1)and GBEE low-does(50 mg·kg-1), medium-does(100 mg·kg-1) and high-does(200 mg·kg-1) groups. The drug were infused to stomach of mice once a day for 14

关键词： GBEE Alzheimer disease scopolamine memory AChE activity

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The mixture of procyanidins extracted from the lotus seed pod and bilobalide ameliorates scopolamine-induced memory impairment in mice

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Neuroscience Bulletin 2009年第4期25卷 203-208页

作者：张丽许继取荣爽谢笔钧孙智达张允建刘烈刚华中科技大学同济医学院附属协和医院神经内科武汉430022 华中科技大学同济医学院公共卫生学院营养与食品卫生学系武汉430022 华中农业大学食品科技学院武汉430070

Objective To study the co-effect of procyanidins extracted from the lotus seed pod （LSPC） and bilobalide （BIL） on ameliorating scopolamine-induced learning and memory impairment in young mice. Methods Fifty male Kunming mice with similar learning and memory capabilities were selected by Morris water maze test and were randomized into 5 groups （n=10 in each group）： control group, scopolamine group, L-（LSPC＋BIL） group （50 mg/kg LSPC＋10 mg/kg BIL）, M-（LSPC＋BIL） group （100 mg/kg LSPC＋20 mg/kg BIL）, H-（LSPC＋BIL） group （150 mg/kg LSPC＋30 mg/kg BIL）. scopolamine model with impaired learning and memory was established by scopolamine treatment （1 mg/kg）, and after 10 min mice were tested. In L-, M-, and H- （LSPC＋BIL） groups, mice were treated with LSPC and BIL ig. for 30 days, while mice in the other 2 groups were treated with normal saline ig. instead. After the 30-day＇s treatment, the co-effect of LSPC and BIL on learning and memory was tested by Morris water maze and the step-down avoidance tests. Results The memory impairment caused by scopolamine in young mice could be ameliorated by co-treatment of LSPC and BIL, as indicated by significantly shorter escape latency and swimming distance in the Morris water maze test, when compared with those in the scopolamine group. In the step-down avoidance test, mice in all the 3 dose groups showed significantly smaller number of errors and longer latency than mice in the scopolamine group did. Conclusion Co-treatment of LSPE and BIL can ameliorate scopolamine-induced learning and memory impairment in young mice.

关键词： lotus seed pod procyanidins bilobalide scopolamine mice learning and memory

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Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy

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Acta Pharmacologica Sinica 2007年第4期28卷 584-590页

作者： Shi-lei CAO Qi-zhi ZHANG Xin-guo JIANG Department of Pharmaceutics,School of Pharmacy,Fudan University,Shanghai 200032,China DepartmentofPharmaceutics SchoolofPharmacyFudanUniversityShanghai200032China

Aim:To develop a novel,in situ gel system for nasal delivery of scopolaminehydrobromide (SCOP) and study its efficacy on motion ***:SCOPin situ gels at 0.2%,0.5%,and 1.0% gellan gum concentration (w/v) were prepared,respectively,and characterized in terms of viscosity,in vitro release,and *** photon emission computing tomography technique was usedto evaluate the nasal residence time of gel containing ~99mTc *** antimotionsickness efficacy produced by the in situ gel formulation was investigated in ratsand compared with those achieved after subcutaneous and oral ***:The viscosity of the gellan gum formulations either in solution or in gelincreased with increasing concentrations of gellan *** release in vitro wasmoderate in artificial nasal *** micrographic results showed that in situ gelswere safe,without nasal *** comparison with phosphate buffer saline,a prolonged radioactivity of99mTc in the rabbit nasal cavity was observed afteradministration of the gellan gum *** SCOP in situ gel at a doseof 100 pg/kg decreased symptoms of motion sickness significantly in comparisonwith subcutaneous and oral administration (P<0.01).Conclusion:SCOP nasal insitu gel is a safe and promising therapeutic alternative to existing medications formotion sickness.

关键词： scopolamine gellan gum nasal delivery motion sickness residence time nasal ciliotoxicity

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Long-term administration of scopolamine interferes with nerve cell proliferation, differentiation and migration in adult mouse hippocampal dentate gyrus, but it does not induce cell death

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Neural Regeneration Research 2014年第19期9卷 1731-1739页

作者： Bing Chun Yan Joon Ha Park Bai Hui Chen Jeong-Hwi Cho In Hye Kim Ji Hyeon Ahn Jae-Chul Lee In Koo Hwang Jun Hwi Cho Yun Lyul Lee Il-Jun Kang Moo-Ho Won Department of Integrative Traditional & Western Medicine Medical CollegeYangzhou University Department of Neurobiology School of MedicineKangwon National University Department of Physiology College of MedicineInstitute of Neurodegeneration and NeuroregenerationHallym University Department of Anatomy and Cell Biology College of Veterinary MedicineSeoul National University Department of Emergency Medicine School of MedicineKangwon National University Department of Food Science and Nutrition Hallym University

Long-term administration of scopolamine, a muscarinic receptor antagonist, can inhibit the survival of newly generated cells, but its effect on the proliferation, differentiation and migration of nerve cells in the adult mouse hippocampal dentate gyrus remain poorly understood. In this study, we used immunohistochemistry and western blot methods to weekly detect the biological behaviors of nerve cells in the hippocampal dentate gyrus of adult mice that received intraperito- neal administration of scopolamine for 4 weeks. Expression of neuronal nuclear antigen （NeuN; a neuronal marker） and Fluoro-]ade B （a marker for the localization of neuronal degeneration） was also detected. After scopolamine treatment, mouse hippocampal neurons did not die, and Ki-67 （a marker for proliferating cells）-immunoreactive cells were reduced in number and reac hed the lowest level at 4 weeks. Doublecortin （DCX; a marker for newly generated neurons）-im- munoreactive cells were gradually shortened in length and reduced in number with time. After scopolamine treatment for 4 weeks, nearly all of the 5-bromo-2＇-deoxyuridine （BrdU）-labeled newly generated cells were located in the subgranular zone of the dentate gyrus, but they did not migrate into the granule cell layer. Few mature BrdU/NeuN double-labeled cells were seen in the subgranular zone of the dentate gyrus. These findings suggest that long-term administration of scopolamine interferes with the proliferation, differentiation and migration of nerve cells in the adult mouse hippocampal dentate gyrus, but it does not induce cell death.

关键词： nerve regeneration neurogenesis scopolamine dentate gyrus cell proliferation neuroblastdifferentiation neuroblast migration granule cell layer neural regeneration

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Low dose transdermal scopolamine increases cardiac vagal tone in patients after acute myocardial infarction

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Chinese Medical Journal 2002年第5期115卷 770-772,158页

作者：王留义王丽霞张永珍张炳勇陈明哲河南省人民医院心内科郑州450003 北京大学第三医院心内科北京100083

OBJECTIVE: To investigate whether transdermal scopolamine increased cardiac vagal activity in patients during the acute phase of myocardial infarction. METHODS: 30 patients with a first acute myocardial infarction and preserved sinus rhythm who were on no drug that could influence the sinus node were randomly assigned to either treatment group or placebo group. Measures of heart rate variability (HRV) in patients given drug or placebo were obtained by digital 24 hour Holter recording before and after treatment. Baroreflex sensitivity was performed using the phenylephrine method. RESULTS: No significant differences was found in the indices of the time domain and the frequency domain in both groups before treatment. Patients with transdermal scopolamine showed a significant increase in the standard deviation of normal RR intervals (SDNN), standard deviation of all five min mean normal RR intervals (SDANN), root mean square of differences of successive normal RR intervals (rMSSD), total power (TP, 0.000. - 0.40 Hz), low frequency peak (LF, 0.040 - 0.15 Hz), high frequency peak (HF, 0.15 - 0.40 Hz), and Baroreflex sensitivity after treatment (P

关键词： Administration, Cutaneous Adult Aged Baroreflex Dose-Response Relationship, Drug Female Heart Heart Rate Humans Male Middle Aged Myocardial Infarction scopolamine Vagus Nerve

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