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Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys

Zoological Research 2020年第1期41卷 3-19页

作者： Pei Zhang Jie-Si Chen Qi-Ye Li Long-Xiang Sheng Yi-Xing Gao Bing-Zheng Lu Wen-Bo Zhu Xiao-Yu Zhan Yuan Li Zhi-Bing Yuan Gang Xu Bi-Tao Qiu Min Yan Chun-Xue Guo You-Qiong Wang Yi-Jun Huang Jing-Xia Zhang Fu-Yu Liu Zhong-Wei Tang Sui-Zhen Lin David NCooper Huan-Ming Yang Jian Wang Yu-Qi Gao Wei Yin Guo-Jie Zhang Guang-Mei Yan State Key Laboratory of Genetic Resources and Evolution Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China BGI-Shenzhen ShenzhenGuangdong 518083China Section for Ecology and Evolution Department of BiologyUniversity of CopenhagenCopenhagen DK-2100Denmark Department of Pharmacology Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhouGuangdong 510080China Institute of Medicine and Hygienic Equipment for High Altitude Region College of High Altitude Military MedicineThird Military Medical UniversityChongqing 400038China Key Laboratory of High Altitude Medicine of People's Liberation Army Chongqing 400038China Key Laboratory of High Altitude Environmental Medicine Third Military Medical UniversityMinistry of EducationChongqing 400038China School of Pharmaceutical Sciences Sun Yat-Sen UniversityGuangzhouGuangdong 510006China Guangzhou Cellprotek Pharmaceutical Co.Ltd. GuangzhouGuangdong 510663China Institute of Medical Genetics School of MedicineCardiff UniversityCardiff CF144XNUK James D.Watson Institute of Genome Sciences HangzhouZhejiang 310058China Department of Biochemistry Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhouGuangdong 510080China Center for Excellence in Animal Evolution and Genetics Chinese Academy of SciencesKunmingYunnan 650223China China National Genebank BGI-ShenzhenShenzhenGuangdong 518120China

Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys (Macaca fascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3β,5,6β-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.

关键词： Acute hypobaric hypoxia cynomolgus monkeys Brain injury Neuroprotectant Gene regulatory networks

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Characterizing the induction of diabetes in juvenile cynomolgus monkeys with different doses of streptozotocin

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Science China(Life Sciences) 2012年第3期55卷 210-218页

作者： ZOU ChunLin WANG JiaYin WANG ShuYan HUANG Fen REN ZhenHua CHEN ZhiGuo ZHANG YU Cell Therapy Center Xuanwu HospitalCapital Medical UniversityBeijing 100053China Key Laboratory of Neurogeneration Ministry of EducationBeijing 100053China Center for Translational Medicine Guangxi Medical UniversityGuangxi 530021China Guangxi Nanning Wincon TheraCeUs Biotechnologies Co. Guangxi 530003China

Juvenile （2-3 years old） cynomolgus monkeys are frequently used as recipients in non-human primate islet transplantation studies. The aim of this study was to examine the effects of different doses of streptozotocin （STZ）, and find the optimal dose for inducing diabetes in these monkeys. Fifteen juvenile （2-3 years old） cynomolgus monkeys were separated into three groups and administered with different doses of STZ （100, 68 or 60 mg kg-l）. Basal and glucose-stimulated blood glucose, in- sulin, and C-peptide levels, as well as body weights were monitored. Hepatic and renal function tests and pancreatic immuno- histochemistry were performed before and after STZ treatment. monkeys treated with both 100 and 68 mg kg-1 of STZ exhib- ited continuous hyperglycemia, which coincided with a nearly complete loss of islet 13-cells. Two monkeys received 60 mg kg-1 of STZ, but only one became completely diabetic. During the first week following STZ treatment, hepatic and renal func- tion slightly increased in these three groups. However. 24 hours post-STZ, serum total bile acid levels were significantly in- creased in monkeys treated with 100 mg kg-1 than those treated with 68 mg kg-I of STZ （P〈0.05）. These data suggest that 100 mg kg-1 and 68 mg kg-1 of STZ can safely induce diabetes in cynomolgus monkeys aged 2-3 years, but 68 mg kg-1 of STZ, rather than 100 mg kg-1 of STZ, may be more appropriate for inducing diabetes in these monkeys. Furthermore, body surface area, rather than body weight, was a more reliable determinant of dosage, where 700 mg m-2 of STZ should be the lower limit for inducing diabetes in juvenile monkeys.

关键词： cynomolgus monkeys diabetes streptozotocin

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MPTP Induces Systemic Parkinsonism in Middle-Aged cynomolgus monkeys:Clinical Evolution and Outcomes

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Neuroscience Bulletin 2017年第1期33卷 17-27页

作者： Feng Yue Sien Zeng Rongping Tang Guoxian Tao Piu Chan Department of Neurobiology Beijing Institute of GeriatricsXuanwu Hospital of Capital Medical UniversityBeijing 100053China Key Laboratory on Parkinson's Disease Beijing 100053China Department of Pathology Guilin Medical CollegeGuilin 541001China Wincon Thera Cells Biotechnologies Co. Ltd.Nanning 530003China

In this study, we developed a systemic PD model in middle-aged cynomolgus monkeys using individualized low-dose MPTP, to explore effective indicators for the early prediction of clinical outcomes. MPTP was not stopped until the animals showed typical PD motor symptoms on days 10 to 13 after MPTP administration when the Kurlan score reached 10; this abrogated the dif- ferences in individual susceptibility to MPTP. The clinical symptoms persisted, peaking on days 3 to 12 after MPTP withdrawal （rapid progress stage）, and then the Kurlan score plateaued. A Kurlan score at the end of the rapid progress stage 〉15 reflected stable or slowly-progressive PD, while a score 〈15 indicated spontaneous recovery. The entire clinical evolution and outcome of the systemic PD model was characterized in this study, thus providing options for therapeutic and translational research.

关键词： Parkinson's disease cynomolgus monkeys MPTP Motor behavior Spontaneous recovery Clinicalevolution

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A natural model of behavioral depression in postpartum adult female cynomolgus monkeys (Macaca fascicularis)

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Zoological Research 2014年第3期35卷 174-181页

作者： Xun-Xun CHU Joshua Dominic Rizak Shang-Chuan YANG Jian-Hong WANG Yuan-Ye MA Xin-Tian HU Laboratory of Primate Neuroscience Research and Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences& Yunnan Province Kunming Institute of Zoology University of the Chinese Academy of Sciences Kunming Primate Research Center Kunming Institute of Zoology Chinese Academy of Sciences

Postpartum depression （PPD） is a modified form of major depressive disorders （MDD） that can exert profound negative effects on both mothers and infants than MDD. Within the postpartum period, both mothers and infants are susceptible; but because PPD typically occurs for short durations and has moderate symptoms, there exists challenges in exploring and addressing the underlying cause of the depression. This fact highlights the need for relevant animal models. In the present study, postpartum adult female cynomolgus monkeys （Macaca fascicularis） living in breeding groups were observed for typical depressive behavior. The huddle posture behavior was utilized as an indicator of behavioral depression postpartum （BDP） as it has been established as the core depressive-like behavior in primates. monkeys were divided into two groups： A t3DP group （n=6）, which were found to spend more time huddling over the first two weeks postpartum than other individuals that formed a non-depression control group （n=4）. The two groups were then further analyzed for locomotive activity, stressful events, hair cortisol levels and for maternal interactive behaviors. No differences were found between the BDP and control groups in locomotive activity, in the frequencies of stressful events experienced and in hair cortisol levels. These findings suggested that the postpartum depression witnessed in the monkeys was not related to external factors other than puerperium period. Interestingly, the BDP monkeys displayed an abnormal maternal relationship consisting of increased infant grooming. Taken together, these findings suggest that the adult female cynomolgus monkeys provide a natural model of behavioral postpartum depression that holds a number of advantages over commonly used rodent systems in PPD modeling. The cynomolgus monkeys have a highly-organized social hierarchy and reproductive characteristics without seasonal restriction--similar to humans--as well as much greater homology to humans

关键词： Postpartum depression cynomolgus monkeys Huddle behavior Locomotion activity Stressful events Hair cortisol Maternal relationship

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Effects of Transportation on Antioxidant Status in cynomolgus monkeys(Macaca fascicularis)

Effects of Transportation on Antioxidant Status in Cynomolgu...

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第十三届中国实验动物科学年会

作者： Xueying Pan Liang Lu Xiancheng Zeng Yan Chang Xiuguo Hua Shanghai Key Laboratory of Veterinary Biotechnology School of Agriculture and BiologyShanghai Jiaotong University National Shanghai Center for New Drug Safety Evaluation&Research(NCDSER)

To evaluate the effects of transportation on oxidative stress in cynomolgus monkeys, the levels of serum reduced glutathione(GSH), malondialdehyde(MDA), and protein carbonyl(PC), and the activities of total antioxidant capacity(T-AOC), superoxide dismutase(SOD), glutathione peroxidase(GSH-Px), and catalase(CAT) in cynomolgus monkeys were examined at the pre-transportation(Day 0), on the day of arrival(Day 1), and on Days 7, 14, and 21 post-transportation. Compared with that on Day 0, T-AOC activity on Days 1, 7, and 14 post-transportation showed a significant decrease(Pcynomolgus monkeys after transportation. These results suggested that transportation could result in imbalance of oxidant and antioxidant and excess oxidative stress in cynomolgus monkeys. cynomolgus monkeys after transportation should have at least 21 days’ recovery to regain their healthy status.

关键词： cynomolgus monkeys transportation oxidative parameters,stress

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