Na+-Ca2+ exchanger mediates Ca2+ influx during anoxia in mammalian central nervous system white matter

Authors

  • Dr. Peter K. Stys MD, FRCS(C),

    Corresponding author
    1. Department of Neurology, Yale University School of Medicine, New Haven, and Neuroscience Research Center (127A), Veterans Administration Hospital, West Haven, CT
    • Yale University School of Medicine, Department of Neurology, 710 LCI, 333 Cedar Street, New Haven, CT 06510
    Search for more papers by this author
  • Stephen G. Waxman MD, PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, and Neuroscience Research Center (127A), Veterans Administration Hospital, West Haven, CT
    Search for more papers by this author
  • Bruce R. Ransom MD, PhD

    1. Department of Neurology, Yale University School of Medicine, New Haven, and Neuroscience Research Center (127A), Veterans Administration Hospital, West Haven, CT
    Search for more papers by this author

Abstract

White matter of the mammalian central nervous system suffers irreversible injury after prolonged anoxia, which can result in severe neurological impairment. This type of injury is critically dependent on Ca2+ influx into cells. We present evidence that the Na+, Ca2+ exchanger mediates the majority of the damaging Ca2+ influx into cells during anoxia in white matter. Anoxic injury was studied in the isolated rat optic nerve, and functional recovery was monitored using the compound action potential. Blockers of voltage-gated Na+ channels (tetrodotoxin and saxitoxin) significantly improved recovery, as did perfusion with zero[BOND]Na+ solution; both maneuvers would prevent intracellular [Na+] from rising and thus prevent Ca2+ influx by inhibiting reverse operation of the Na+, Ca2+ exchanger. Direct pharmacological blockade of the Na+, Ca2+ exchanger during anoxia with bepridil or benzamil also significantly improved recovery. These findings suggest that reverse operation of the Na+, Ca2+ exchanger during anoxia is a critical mechanism of Ca2+ influx and subsequent white matter injury.

Ancillary