Identifying the dataset to define the optimal timing of histopathological examination for central nervous system toxicity in MPTP-induced Parkinson’s disease monkey model

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  • Yasuno Hironobu
    Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
  • Masuda Yasushi
    Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
  • Ozaki Harushige
    Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
  • Sano Tomoya
    Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
  • Shinozawa Tadahiro
    Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan
  • Watanabe Takeshi
    Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan

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<p> Determining the optimal timing for histopathological examination following exposure to a test article is crucial for assessing neurotoxicity. However, no study has focused on identifying an ideal dataset to define the optimal timing for histopathological examination of central nervous system (CNS) toxicity in monkeys. Therefore, this study aimed to define a predictive endpoint that would guide us in selecting the optimal timing for histopathological examination of CNS toxicity in monkeys. Four cynomolgus monkeys were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously at a dosage of 0.6 mg/kg twice at 1-week intervals. Necropsies were performed 1 week after the final dose. The Parkinsonian rating (PR) score and temporal changes in neurofilament light chain and glial fibrillary acidic protein concentrations in the cerebrospinal fluid (CSF) and serum were evaluated and compared with the histopathological findings in the brain. The PR score of all animals administered MPTP increased from days 10 to 11, with some degree of individual variability. Microscopically, all animals showed axonal swelling and vacuolation, with or without microgliosis in the nigrostriatal bundle. However, substantial neurodegenerative findings were observed only in animals with high PR scores at necropsy. A slight increase in CSF biomarker levels at necropsy was also observed in animals with high PR scores. However, their correlation with microscopic findings in these animals was unclear. These data suggest that comprehensive clinical observations, such as PR score alone or combined with other CSF biomarkers, could be further evaluated as potential indicators for triggering anatomic CNS evaluations in monkeys following toxic insults.</p>

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