Recovery from Coma Post-Cardiac Arrest Is Dependent on the Orexin Pathway

Cardiac arrest (CA) affects >550,000 people annually in the United States whereas 80-90% of survivors suffer from a comatose state. Arousal from coma is critical for recovery, but mechanisms of arousal are undefined. Orexin-A, a hypothalamic excitatory neuropeptide, has been linked to arousal deficits in various brain injuries. We investigated the orexinergic system's role in recovery from CA-related neurological impairments, including arousal deficits. Using an asphyxial CA and resuscitation model in rats, we examine neurological recovery post-resuscitation in conjunction with changes in orexin-A levels in cerebrospinal fluid (CSF) and orexin-expressing neurons. We also conduct pharmacological inhibition of orexin post-resuscitation. We show that recovery from neurological deficits begins between 4 and 24 h post-resuscitation, with additional recovery by 72 h post-resuscitation. Orexin-A levels in the CSF are lowest during periods of poorest arousal post-resuscitation (4 h) and recover to control levels by 24 h. Immunostaining revealed that the number of orexin-A immunoreactive neurons declined at 4 h post-resuscitation, but increased to near normal levels by 24 h. There were no significant changes in the number of neurons expressing melanin-concentrating hormone, another neuropeptide localized in similar hypothalamus regions. Last, administration of the dual orexin receptor antagonist, suvorexant, during the initial 24 h post-resuscitation, led to sustained neurological deficits. The orexin pathway is critical during early phases of neurological recovery post-CA. Blocking this early action leads to persistent neurological deficits. This is of considerable clinical interest given that suvorexant recently received U.S. Food and Drug Administration approval for insomnia treatment.