Cellular Stress And Ampk Activators Including Metformin And The Anesthetic Drug Propofol Promote Restoration Of Human Consciousness

The neural mechanisms that give rise to human consciousness have been described as one of the greatest and most profound mysteries in all of modern medicine.  The use of general anesthetics to induce loss of consciousness (LOC) in millions of patients each year provides a unique opportunity to determine if various neural circuits play critical roles in the promotion or restoration of consciousness.

Many general anesthetics, including propofol, the most widely-used anesthetic to induce and/or maintain general anesthesia in humans, induce LOC in part by potentiating chloride influx through the GABAA receptor, leading to neural inhibition. During the initial period of general anesthesia, known as induction, a bolus dose of an anesthetic drug is administered that leads to LOC. Consciousness is characterized by wakefulness, arousal, cognition, self-awareness, and awareness of one’s environment.  LOC may be easily assessed by a patient’s lack of response to a verbal command from a clinician.

Interestingly, an intriguing phenomenon known as paradoxical excitation may also occur after initial administration of an anesthetic drug.  As the name implies, nearly every anesthetic drug used clinically may paradoxically excite the brain before inducing unconsciousness (e.g. eccentric body movements, transient increases in beta activity on the electroencephalogram, etc.). Anesthesiologists and neuroscientists are currently unable to explain how anesthetics are able to induce paradoxical excitation.

Additionally, emergence from general anesthesia is a passive process that occurs after anesthetic removal, is associated with lower levels of anesthetic concentrations in the brain, and is also characterized by transient increases in beta activity on the electroencephalogram just before emergence, similar to low dose anesthetic-induced paradoxical excitation just before loss of consciousness.  Such evidence indicates that paradoxical excitation and the period just before emergence from general anesthesia are analogous and that both states may indeed share a common mechanism.

AMPK is an evolutionarily conserved kinase that increases lifespan and healthspan in several model organisms, is present throughout the mammalian brain, and is activated by increases in cellular stress (e.g. increases in calcium [Ca2+], reactive oxygen species [ROS], and/or increases in the AMP/ATP ratio, etc.).  Both Ca2+ and ROS play critical roles in neuronal excitation and the inhibition of AMPK has recently been shown to inhibit long-term potentiation in vitro(considered the cellular correlate for learning and memory) and long-term memory formation in vivoin mice. Additionally, glutamate, the primary excitatory neurotransmitter in the human brain, activates AMPK in cortical neurons and nearly every neurotransmitter that is essential for maintaining and/or restoring human consciousness activates AMPK (i.e. acetylcholine, histamine, orexin-A, dopamine, and norepinephrine).

Furthermore, nearly every anesthetic drug used clinically that promotes paradoxical excitation but also induces loss of consciousness in human patients activates AMPK, including propofol, sevoflurane, isoflurane, dexmedetomidine, ketamine, and midazolam. Bicuculline (a secondary metabolite produced by the plant Corydalis chaerophylla) reverses propofol anesthesia and activates AMPK in cortical neurons and several compounds that have been shown to accelerate emergence from anesthesia also activate AMPK (e.g. nicotine, caffeine, forskolin, and carbachol).

Such evidence suggests a novel and provocative hypothesis wherein paradoxical excitation is considered analogous to the period just before emergence from general anesthesia and that cellular stress-induced AMPK activation by low doses of anesthetic drugs and several excitatory neurotransmitters represents a common mechanism of action promoting both states.  Indeed, AMPK activators including metformin and nicotine cross the blood-brain barrier in vivoand enhance the proliferation and differentiation of neural stem cells in the brain, potentially enhancing brain repair and facilitating restoration of consciousness in patients diagnosed with disorders of consciousness (e.g. coma).

Cellular stress-induced AMPK activation may also link human consciousness with other seemingly disparate physiological and pathophysiological processes, including “young blood” (young plasma activates AMPK), pathological aging (metformin activates AMPK and alleviates accelerated aging defects in progeria cells), plasma medicine (cold physical plasma exerts beneficial effects in cells by increasing ROS levels), human life creation (stress-inducing agents promote oocyte maturation and the acrosome reaction in sperm), “jumping genes” (stress promotes the beneficial activation & mobilization of “jumping genes”  in human cells), meditation (meditation increases genes in the AMPK signaling pathway in humans), regeneration of body parts (AMPK and stress play important roles in planarian worm regeneration), and CRISPR-Cas activation in bacteria (stressors including temperature stress and nutrient deprivation activate CRISPR-Cas systems).