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Taking central nervous system regenerative therapies to the clinic: curing rodents versus nonhuman primates versus humans

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Neural Regeneration Research 2020年第3期15卷 425-437页

作者： Magdalini Tsintou Kyriakos Dalamagkas Nikos Makris Departments of Psychiatry and Neurology Services Center for Neural Systems InvestigationsCenter for Morphometric AnalysisAthinoula A.Martinos Center for Biomedical ImagingMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA Department of Psychiatry Psychiatry Neuroimaging LaboratoryBrigham and Women’s HospitalHarvard Medical SchoolBostonMAUSA University College of London Division of Surgery&Interventional Science Center for Nanotechnology&Regenerative MedicineUniversity College LondonLondonUK Department of Physical Medicine and Rehabilitation The University of Texas Health Science Center at HoustonHoustonTXUSA The Institute for Rehabilitation and Research Memorial Hermann Research Center The Institute for Rehabilitation and Research Memorial Hermann HospitalHoustonTXUSA Department of Anatomy&Neurobiology Boston University School of MedicineBostonMAUSA

The central nervous system is known to have limited regenerative *** only does this halt the human body’s reparative processes after central nervous system lesions,but it also impedes the establishment of effective and safe therapeutic options for such *** the high prevalence of stroke and spinal cord injury in the general population,these conditions remain incurable and place a heavy burden on patients’families and on society more *** and neural engineering are diverse biomedical fields that attempt reparative treatments,utilizing stem cells-based strategies,biologically active molecules,nanotechnology,exosomes and highly tunable biodegradable systems(e.g.,certain hydrogels).Although there are studies demonstrating promising preclinical results,safe clinical translation has not yet been accomplished.A key gap in clinical translation is the absence of an ideal animal or ex vivo model that can perfectly simulate the human microenvironment,and also correspond to all the complex pathophysiological and neuroanatomical factors that affect functional outcomes in humans after central nervous system *** an ideal model does not currently exist,but it seems that the nonhuman primate model is uniquely qualified for this role,given its close resemblance to *** review considers some regenerative therapies for central nervous system repair that hold promise for future clinical *** addition,it attempts to uncover some of the main reasons why clinical translation might fail without the implementation of nonhuman primate models in the research pipeline.

关键词： animal models central nervous system regeneration clinical translation exosomes hydrogels neural tissue engineering nonhuman primates spinal cord injury stem cells stroke

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Local transgene expression and whole-body transgenesis to model brain diseases in nonhuman primate

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Animal Models and Experimental Medicine 2019年第1期2卷 9-17页

作者： Lucie Chansel-Debordeaux Erwan Bezard Institut des Maladies Neurodégénératives University of Bordeaux CNRS Institut des Maladies Neurodégénératives CHU Bordeaux Service de Biologie de la reproduction-CECOS

Animal model is an essential tool in the life sciences research, notably in understanding the pathogenesis of the diseases and for further therapeutic intervention success. Rodents have been the most frequently used animals to model human disease since the establishment of gene manipulation technique. However, they remain inadequate to fully mimic the pathophysiology of human brain disease, partially due to huge differences between rodents and humans in terms of anatomy, brain function, and social behaviors. nonhuman primates are more suitable in translational perspective. Thus, genetically modified animals have been generated to investigate neurologic and psychiatric disorders. The classical transgenesis technique is not efficient in that model; so, viral vector-mediated transgene delivery and the new genome-editing technologies have been promoted. In this review, we summarize some of the technical progress in the generation of an ad hoc animal model of brain diseases by gene delivery and real transgenic nonhuman primate.

关键词： animal models neuroscience nonhuman primates

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Technology advancing the study of animalcognition： using virtual reality to presentvirtually simulated environments to investigatenonhuman primate spatial cognition

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Current Zoology 2017年第1期63卷 97-108页

作者： Francine L. DOLINS Kenneth SCHWELLER Scott MILNE Department of Behavioral Sciences University of Michigan-Dearborn Dearborn MI 48128 USA Ape Cognition and Conservation Initiative Des Moines IA USA Impact Madagascar Nanisana Antananarivo 101Madagascar Africa

Virtual simulated environments provide multiple ways of testing cognitive function and evaluatingproblem solving with humans （e.g., Woollett et al. 2009）. The use of such interactive technologyhas increasingly become an essential part of modern life （e.g., autonomously driving vehicles, glo-bal positioning systems （GPS）, and touchscreen computers; Chinn and Fairlie 2007; Brown 2011）.While many nonhuman animals have their own forms of technology, such as chimpanzees whocreate and use tools, in captive animal environments the opportunity to actively participate withinteractive technology is not often made available. Exceptions can be found in some state-of-the-art zoos and laboratory facilities （e.g., Mallavarapu and Kuhar 2005）. When interactive technologyis available, captive animals often selectively choose to engage with it. This enhances the animal＇ssense of control over their immediate surroundings （e.g., Clay et al. 2011; Ackerman 2012）. Suchself-efficacy may help to fulfill basic requirements in a species＇ daily activities using problem solv-ing that can involve foraging and other goal-oriented behaviors. It also assists in fulfilling thestrong underlying motivation for contrafreeloading and exploration expressed behaviorally bymany species in captivity （Young 1999）. Moreover, being able to present nonhuman primates vir-tual reality environments under experimental conditions provides the opportunity to gain insightinto their navigational abilities and spatial cognition. It allows for insight into the generation andapplication of internal mental representations of landmarks and environments under multiple con-ditions （e.g., small- and large-scale space） and subsequent spatial behavior. This paper reviewsmethods using virtual reality developed to investigate the spatial cognitive abilities of nonhumanprimates, and great apes in particular, in comparison with that of humans of multiple age *** make recommendations about training, best practices, and also pi

关键词： animal cognition, apes, bonobos, chimpanzees, nonhuman primates, spatial cognition, virtual reality.

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In vitro and in vivo models of acute alcohol exposure

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World Journal of Gastroenterology 2009年第10期15卷 1168-1177页

作者： Angela Dolganiuc Gyongyi Szabo Department of Medicine University of Massachusetts Medical School 364 Plantation Street Worcester MA 01605-2324 United States

Alcohol abuse is a global problem due to the financial burden on society and the healthcare system. While the harmful health effects of chronic alcohol abuse are well established, more recent data suggest that acute alcohol consumption also affects human wellbeing. Thus, there is a need for research models in order to fully understand the effect of acute alcohol abuse on different body systems and organs. The present manuscript summarizes the interdisciplinary advantages and disadvantages of currently available human and non-human models of acute alcohol abuse, and identifi es their suitability for biomedical research.

关键词： Models Acute alcohol abuse Human nonhuman Progress

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Induction of diabetes in cynomolgus monkey with one shot of analytical grade streptozotocin

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Animal Models and Experimental Medicine 2020年第1期3卷 79-86页

作者： Zhengzhao Liu Ying Lu Wenbao Hu Hidetaka Hara Yifan Dai Zhiming Cai Lisha Mou Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational MedicineShenzhen Second People's HospitalThe First Affiliated Hospital of Shenzhen UniversityHealth Science CenterShenzhenChina Movement System Injury and Repair Research Center Xiangya Hospital of Central South UniversityChangshaChina Jiangsu Key Laboratory of Xenotransplantation Nanjing Medical UniversityNanjingChina Xenotransplantation Program/Department of Surgery The University of Alabama at BirminghamBirminghamALUSA

Backgrounds:Streptozotocin(STZ)-induced diabetic monkey is a wide used preclinical animal model for the investigation of diabetes such as islet transplantation and development of diabetic *** are serious side effects of this method,including nausea,emesis,weight loss,liver damage,renal failure,and metabolic *** order to reduce the side effects,diabetic monkeys were induced using clinicalgrade ***,clinical-grade STZ is not available in ***,we establised a method by using 100 mg/kg analytical-grade STZ to induce complete diabetes in cynomolgus monkey without generating adverse effects to liver and ***:Three cynomolgus monkeys were used in this study.100 mg/kg STZ dissolved in normal saline and infused through vein line in 5 minutes after indwelling catheter in the carotid artery and jugular *** the STZ administration,blood glucose levels were examined every 1 or 2 hours in the first 48 ***,blood glucose levels were examined twice per day during the first week after the STZ *** and C-peptide levels were measured by *** chemistry of hepatic and renal function tests were *** and glucagon expression in the islet of diabetic monkey and normal monkey were examined by immunohistochemistry ***:The stimulated C-peptide level(Intravenous glucose tolerance test)which is less than 0.5 ng/mL,the triphasic blood glucose response and the destroyed β cell suggested the complete induction of diabetes *** apparent adverse effects were observed including no signs of vomiting and toxicity after STZ ***:In summary,we established a safe and reproducible STZ-induced diabetic cynomolgus monkey model for islet transplantation which will be used to develop novel approaches for the treatment of diabetes.

关键词： analytical grade diabetic model nonhuman primate STZ

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Relationship between Age and Neurogenesis in Old World Monkeys

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Neuroscience & Medicine 2013年第3期4卷 172-180页

作者： Tarique D. Perera Arkadiy Yaretskiy Anna V. Rozenboym Zeena Audi Cecilia Lipira Jean Tang Jeremy Hill Lakshmi Thirumangalakudi Daniel C. Lee Andrew J. Dwork Jeremy D. Coplan Department of Biological Sciences Kingsborough Community College Brooklyn USA Departments of Psychiatry College of Physicians and Surgeons Columbia University Medical Center and New York State Psychi- atric Institute New York USA Division of Cardiothoracic Surgery SUNY Downstate Medical Center Brooklyn USA nonhuman Primate Facility Department of Psychiatry SUNY Downstate Medical Center Brook- lyn USA

Hippocampal neurogenesis continues throughout the lifespan of adult mammals, but the rates decline dramatically with increasing age. Among the factors that have been shown to affect neurogenesis, aging has been shown to be one of its most potent regulators in mice. The mechanism for the decline in neurogenesis with age is thought to be related to age-dependent changes in local and systemic neuroendocrinology and neurochemistry, as well as internal changes to precursor cells that result in decreased reactivity to normal stimuli. Since most of the data about neurogenesis and age were established from rodent studies, we sought to study this relationship in nonhuman primates in five previously studied cohorts of bonnet monkeys (Macaca radiata). In the present study, we statistically analyze the relationship of age and hippocampal neurogenesis rates, as measured by the number of DCX expressing cells in the subgranular zone of the dentate gyrus in 71 subjects with ages ranging from 3.5 to 17 years. We observed a non-significant relationship between age and doublecortin for subjects less than nine years old (corresponding to young and full adulthood) but a linear significant decline for subjects 9 years or greater (middle age and senescence). In contrast to previous studies that show neurogenesis to decline linearly throughout the lifespan, this study shows that neurogenesis occurs steadily throughout adulthood and begins to decline in middle age in bonnet macaques.

关键词： Neurogenesis Age Macaca Radiate nonhuman Primates

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