Jincheol Seo1, Youngjeon Lee2, Bom Sahn Kim3, Junghyung Park4, Sejung Yang5, Hai-Jeon Yoon3, Jang Yoo3, Hyun Soo Park6, Jung-Joo Hong4, Bon-Sang Koo4, Seung Ho Baek4, Chang-Yeop Jeon4, Jae-Won Huh2, Young-Hyun Kim2, Sang Je Park4, Jinyoung Won4, Yu-Jin Ahn2, Keonwoo Kim7, Kang Jin Jeong4, Philyong Kang4, Dong-Seok Lee8, Soo Mee Lim9, Yeung Bae Jin10, Sang-Rae Lee11. 1. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea. 2. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, Republic of Korea. 3. Department of Nuclear medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea. 4. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea. 5. Department of Biomedical Engineering, Yonsei University, Wonju 220-710, Republic of Korea. 6. Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea. 7. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Physical Therapy, Graduate School of Inje University, Gimhae, Republic of Korea. 8. School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea. 9. Department of Radiology, Ewha Womans University School of Medicine, Seoul, Republic of Korea. Electronic address: soomee@ewha.ac.kr. 10. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea. Electronic address: ybjin@kribb.re.kr. 11. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, Republic of Korea. Electronic address: srlee@kribb.re.kr.
Abstract
BACKGROUND: The guidelines for applying individual adjustments to macaques according to the severity of behavioral symptoms during 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment were provided to reproduce stable chronic Parkinsonism in a recent study (Potts et al., 2014). But, since there are insufficient guidelines regarding objective severity criteria of individual symptoms for adjustments of MPTP treatment, it is difficult to develop MPTP-induced chronic non-human primate (NHP) models with stable symptoms. NEW METHOD: The individual adjustments of MPTP administration based on results of automatic quantification of global activity (GA) using a video-based tracking system were applied to develop MPTP-PD model. Low-dose (0.2 mg/kg) intramuscular injection was repeated continuously until GA was lower than 8% of baseline Parkinsonian behavior scores. The positron emission tomography imaging were used to follow the longitudinal course of Parkinson's disease (PD). RESULTS: Significant reductions in GA and dopamine transporter activity, along with significant increases in Parkinsonian behavior scores were found from 4 to 48 weeks following the first administration. GA was correlated with the Parkinsonian behavior score. The dopamine transporter activity was correlated with GA and the Parkinsonian behavior score. However, it was not correlated with the total dose of MPTP. Damage of dopaminergic neuronal systems in the basal ganglia was confirmed by immunohistochemistry and Western blot. COMPARISON WITH EXISTING METHOD: This study reinforces previous guidelines regarding production of NHP models with stable Parkinsonian symptoms. CONCLUSIONS: This novel strategy of MPTP administration based on global activity evaluations provides an important conceptual advance for the development of chronic NHP Parkinsonian models.
BACKGROUND: The guidelines for applying individual adjustments to macaques according to the severity of behavioral symptoms during 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment were provided to reproduce stable chronic Parkinsonism in a recent study (Potts et al., 2014). But, since there are insufficient guidelines regarding objective severity criteria of individual symptoms for adjustments of MPTP treatment, it is difficult to develop MPTP-induced chronic non-human primate (NHP) models with stable symptoms. NEW METHOD: The individual adjustments of MPTP administration based on results of automatic quantification of global activity (GA) using a video-based tracking system were applied to develop MPTP-PD model. Low-dose (0.2 mg/kg) intramuscular injection was repeated continuously until GA was lower than 8% of baseline Parkinsonian behavior scores. The positron emission tomography imaging were used to follow the longitudinal course of Parkinson's disease (PD). RESULTS: Significant reductions in GA and dopamine transporter activity, along with significant increases in Parkinsonian behavior scores were found from 4 to 48 weeks following the first administration. GA was correlated with the Parkinsonian behavior score. The dopamine transporter activity was correlated with GA and the Parkinsonian behavior score. However, it was not correlated with the total dose of MPTP. Damage of dopaminergic neuronal systems in the basal ganglia was confirmed by immunohistochemistry and Western blot. COMPARISON WITH EXISTING METHOD: This study reinforces previous guidelines regarding production of NHP models with stable Parkinsonian symptoms. CONCLUSIONS: This novel strategy of MPTP administration based on global activity evaluations provides an important conceptual advance for the development of chronic NHP Parkinsonian models.