Combination of pathological, biochemical and behavioral evaluations for peripheral neurotoxicity assessment in isoniazid-treated rats

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  • Kashimura Akane
    Safety Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara-shi, Kanagawa 252-5201, Japan
  • Nishikawa Satomi
    Safety Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan
  • Ozawa Yuhei
    Safety Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan
  • Hibino Yui
    Safety Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan
  • Tateoka Takashi
    Safety Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan
  • Mizukawa Mao
    Safety Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara-shi, Kanagawa 252-5201, Japan
  • Nishina Hironobu
    Safety Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan
  • Sakairi Tetsuya
    Safety Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa 251-8555, Japan
  • Shiga Takanori
    Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara-shi, Kanagawa 252-5201, Japan
  • Aihara Naoyuki
    Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara-shi, Kanagawa 252-5201, Japan
  • Kamiie Junichi
    Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara-shi, Kanagawa 252-5201, Japan

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<p> In drug development, assessment of non-clinical peripheral neurotoxicity is important to ensure human safety. Clarifying the pathological features and mechanisms of toxicity enables the management of safety risks in humans by estimating the degree of risk and proposing monitoring strategies. Published guidelines for peripheral neurotoxicity assessment do not provide detailed information on which endpoints should be monitored preferentially and how the results should be integrated and discussed. To identify an optimal assessment method for the characterization of peripheral neurotoxicity, we conducted pathological, biochemical (biomaterials contributing to mechanistic considerations and biomarkers), and behavioral evaluations of isoniazid-treated rats. We found a discrepancy between the days on which marked pathological changes were noted and those on which biochemical and behavioral changes were noted, suggesting the importance of combining these evaluations. Although pathological evaluation is essential for pathological characterization, the results of biochemical and behavioral assessments at the same time points as the pathological evaluation are also important for discussion. In this study, since the measurement of serum neurofilament light chain could detect changes earlier than pathological examination, it could be useful as a biomarker for peripheral neurotoxicity. Moreover, examination of semi-thin specimens and choline acetyltransferase immunostaining were useful for characterizing morphological neurotoxicity, and image analysis of semi-thin specimens enabled us to objectively show the pathological features.</p>

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