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Central nervous system stimulants promote nerve cell death under continuous hypoxia

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Abstract

Intake of central nervous system (CNS) stimulants causes hypoxia and brain edema, which results in nerve cell death. However, no study has yet investigated the direct and continuous effects on nerve cells of CNS stimulants under hypoxia. Thus, based on autopsy cases, the effects of CNS stimulant drugs on the CNS were examined. The pathological changes in cultured nerve cells when various CNS stimulants were added under a hypoxic condition were also investigated. Five groups (Group A, stimulants; Group B, stimulants with psychiatric drugs; Group C, caffeine; Group D, psychiatric drugs; and Group E, no drugs) according to the detected drugs in autopsy cases were compared, and brain edema was evaluated using morphological findings. Furthermore, the number of dead cultured nerve cells was counted after the addition of drugs (4-aminopyridine (4-AP), caffeine, and ephedrine) under hypoxia (3% O2). Staining with anti-receptor-interacting protein 3 (RIP3) and other associated stains was also performed to investigate the neuronal changes in the brain. Group A showed significantly more brain edema than the other groups. In the culture experiments, the ratio of nerve cell death after the addition of 4-AP was the highest in the hypoxic condition. Groups with stimulants detected were stained more strongly by RIP3 immunostaining than by other staining. Addition of stimulants to cultured nerve cells in a persistent hypoxic condition led to severe cytotoxicity and nerve cell death. These findings suggest that necroptosis is involved in nerve cell death due to the addition of CNS stimulants in the hypoxic condition.

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Authors and Affiliations

  1. Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan

    Kei Ikeda-Murakami

  2. Department of Legal Medicine, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan

    Tomoya Ikeda, Naoto Tani & Takaki Ishikawa

  3. Forensic Autopsy Section, Medico-Legal Consultation and Postmortem Investigation Support Center, Department of Legal Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan

    Tomoya Ikeda, Naoto Tani & Takaki Ishikawa

  4. Laboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of Medicine, Health and Medical Science Innovation Laboratory 403, University of Tsukuba, Tsukuba City, Ibaraki, 305-8575, Japan

    Miho Watanabe

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  1. Kei Ikeda-Murakami
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Correspondence to Kei Ikeda-Murakami.

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Ethics approval

This study was evaluated by the Independent Ethics Committee of the Osaka City University Graduate School of Medicine. Informed consent form opt-out for the autopsy data analysis was approved by the Independent Ethics Committee of Osaka City University Graduate School of Medicine (authorization no. 2001). The Ethics Committee approval for the study is valid for the period from April 5, 2011, to March 31, 2038.

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The authors complied with the ethics approval (authorization no.2001) that was obtained from the Independent Ethics Committee of the Osaka City University Graduate School of Medicine regarding informed consent for publication of the case details.

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Ikeda-Murakami, K., Ikeda, T., Watanabe, M. et al. Central nervous system stimulants promote nerve cell death under continuous hypoxia. Human Cell 35, 1391–1407 (2022). https://doi.org/10.1007/s13577-022-00734-0

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