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Probing the molecular mechanisms of neuronal degeneration: importance of mitochondrial dysfunction and calcineurin activation

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Abstract

Cerebral injury is a critical aspect of the management of patients in intensive care. Pathological conditions induced by cerebral ischemia, hypoxia, head trauma, and seizure activity can result in marked residual impairment of cerebral function. We have investigated the potential mechanisms leading to neuronal cell death in pathological conditions, with the aim of discovering therapeutic targets and methods to minimize neuronal damage resulting from insults directed at the central nervous system (CNS). Over the years, deeper understanding of the mechanisms of neuronal cell death has indeed evolved, enabling clinical critical care management to salvage neurons that are at the brink of degeneration and to support recovery of brain function. However, no substantial breakthrough has been achieved in the quest to develop effective pharmacological neuroprotective therapy directed at tissues of the CNS. The current situation is unacceptable, and preservation of function and protection of the brain from terminal impairment will be a vital medical issue in the twenty-first century. To achieve this goal, it is critical to clarify the key mechanisms leading to neuronal cell death. Here, we discuss the importance of the calcineurin/immunophilin signal transduction pathway and mitochondrial involvement in the detrimental chain of events leading to neuronal degeneration.

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Authors and Affiliations

  1. Department of Anesthesiology, Hachioji Medical Center, Tokyo Medical University, 1163 Tate-machi, Hachioji, Tokyo, 193-0998, Japan

    Hiroyuki Uchino, Saori Morota, Go Hirabayashi, Nagao Ishii & Yukiho Ikeda

  2. Emergency Medical Center, Kagawa University Hospital, Kagawa, Japan

    Yasuhiro Kuroda

  3. Laboratory for Experimental Brain Research, Department of Clinical Sciences, Lund University, Lund, Sweden

    Saori Morota, Magnus J. Hansson & Eskil Elmér

  4. Laboratory of Cellular Neurobiology, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

    Saori Morota

  5. Department of Molecular Physiology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Futoshi Shibasaki

Authors
  1. Hiroyuki Uchino
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  2. Yasuhiro Kuroda
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  3. Saori Morota
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  4. Go Hirabayashi
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  5. Nagao Ishii
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  6. Futoshi Shibasaki
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  7. Yukiho Ikeda
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  8. Magnus J. Hansson
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  9. Eskil Elmér
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Additional information

Commercial declaration: author E.E. is founder of Maas BiolAB, LLC, and NeuroVive Pharmaceutical AB (formerly named NeuroPharma AB), which hold intellectual property rights and develop the use of cyclosporins for neurological treatment.

This review article was invited by the Editorial Board members of the Journal of Anesthesia and was peer-reviewed as were the other articles in this journal.

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Uchino, H., Kuroda, Y., Morota, S. et al. Probing the molecular mechanisms of neuronal degeneration: importance of mitochondrial dysfunction and calcineurin activation. J Anesth 22, 253–262 (2008). https://doi.org/10.1007/s00540-008-0617-3

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  • DOI: https://doi.org/10.1007/s00540-008-0617-3

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