Cellular stress and AMPK links metformin and diverse compounds with accelerated emergence from anesthesia and potential recovery from disorders of consciousness.

The neural correlates of consciousness and the mechanisms by which general anesthesia (GA) modulate such correlates to induce loss of consciousness (LOC) has been described as one of the biggest mysteries of modern medicine. Several cellular targets and neural circuits have been identified that play a critical role in LOC induced by GA, including the GABAA receptor and ascending arousal nuclei located in the basal forebrain, hypothalamus, and brain stem. General anesthetics (GAs) including propofol and inhalational agents induce LOC in part by potentiating chloride influx through the GABAA receptor, leading to neural inhibition and LOC. Interestingly, nearly all GAs used clinically may also induce paradoxical excitation, a phenomenon in which GAs promote neuronal excitation at low doses before inducing unconsciousness. Additionally, emergence from GA, a passive process that occurs after anesthetic removal, is associated with lower anesthetic concentrations in the brain compared to doses associated with induction of GA. AMPK, an evolutionarily conserved kinase activated by cellular stress (e.g. increases in calcium [Ca2+] and/or reactive oxygen species [ROS], etc.) increases lifespan and healthspan in several model organisms. AMPK is located throughout the mammalian brain, including in neurons of the thalamus, hypothalamus, and striatum as well as in pyramidal neurons in the hippocampus and cortex. Increases in ROS and Ca2+ play critical roles in neuronal excitation and glutamate, the primary excitatory neurotransmitter in the human brain, activates AMPK in cortical neurons. Nearly every neurotransmitter released from ascending arousal circuits that promote wakefulness, arousal, and consciousness activates AMPK, including acetylcholine, histamine, orexin-A, dopamine, and norepinephrine. Several GAs that are commonly used to induce LOC in human patients also activate AMPK (e.g. propofol, sevoflurane, isoflurane, dexmedetomidine, ketamine, midazolam). Various compounds that accelerate emergence from anesthesia, thus mitigating problematic effects associated with delayed emergence such as delirium, also activate AMPK (e.g. nicotine, caffeine, forskolin, carbachol). GAs and neurotransmitters also act as preconditioning agents and the GABAA receptor inhibitor bicuculline, which reverses propofol anesthesia, also activates AMPK in cortical neurons. We propose the novel hypothesis that cellular stress-induced AMPK activation links wakefulness, arousal, and consciousness with paradoxical excitation and accelerated emergence from anesthesia. Because AMPK activators including metformin and nicotine promote proliferation and differentiation of neural stem cells located in the subventricular zone and the dentate gyrus, AMPK activation may also enhance brain repair and promote potential recovery from disorders of consciousness (i.e. minimally conscious state, vegetative state, coma).