Metformin shares common mechanism with nearly every Anesthesia drug: AMPK links Consciousness with Jumping Genes & the Creation of Human Life

By ISAF Headquarters Public Affairs Office (originally posted to Flickr as 100410-F-7713A-002) [CC BY 2.0 (https://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons; By Anatomist90 [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], from Wikimedia Commons

A recently published study in the journal PLoS One in May of 2018 demonstrated that the anesthetic drug propofol significantly increased intracellular calcium (Ca2+) levels, induced a burst of reactive oxygen species (ROS), and activated the master metabolic regulator AMPK in C2C12 cells [18]. Similar results were also obtained in a recent study published in April of 2018, wherein propofol also increased intracellular Ca2+ levels and activated AMPK in HeLa cells [105]. AMPK is an evolutionarily conserved protein that increases lifespan and healthspan in several model organisms [34]. Activation of AMPK is also the primary mechanism of action of the anti-diabetic drug metformin, a compound that has displayed wide-raging efficacy in multiple disparate disease states, including cancer, dementia, depression, frailty-related diseases, and cardiovascular diseases [34,106]. Interestingly, propofol is considered one of the most popular and widely-used intravenous anesthetic drugs in modern medicine to induce and maintain general anesthesia in humans [107]. Curiously, a recent study published in the journal Current Biology in June of 2018 by researchers from the University of Michigan demonstrated that the compound carbachol reversed anesthesia induced by the inhaled anesthetic sevoflurane and restored wake-like behavior and level of consciousness in rats [27]. Carbachol is a compound that binds to and stimulates acetylcholine receptors in the brain but also activates AMPK in human cells, similar to both metformin and propofol [27,108].

Each of these studies substantiates several novel proposals in a recently published paper I authored in June of 2018 in which I proposed for the first time that cellular stress-induced AMPK activation links consciousness and accelerated emergence from anesthesia with paradoxical excitation, hippocampal long-term potentiation (essential for learning and memory), alleviation of accelerated cellular aging in Hutchinson-Gilford progeria syndrome, oocyte activation and the sperm acrosome reaction (prerequisites for human life creation), and transposable element (i.e. “jumping genes”)-mediated promotion of learning, memory, and the creation of human life [1-6].

As further explained below, nearly every neurotransmitter that plays a critical role in promoting wakefulness, arousal, and consciousness activates AMPK (glutamate, acetylcholine, orexin-A, histamine, norepinephrine, dopamine, and serotonin) [7-17]. Several drugs that are commonly used to induce and maintain general anesthesia also activate AMPK in low doses (propofol, sevoflurane, isoflurane, ketamine, dexmedetomidine, and midazolam) [18-23]. Also, several compounds that have recently been shown to promote accelerated emergence from anesthesia also activate AMPK (carbachol, orexin-A, histamine, dopamine, dopamine D1 receptor agonists, nicotine, caffeine, and forskolin) [9-11,13,24-33].

AMPK, an evolutionarily conserved kinase that is activated by the induction of cellular stress (i.e. increases in intracellular reactive oxygen species [ROS], calcium [Ca2+], and/or an AMP(ADP)/ATP ratio increase), increases lifespan and healthspan in several model organisms (yeast, worms, flies, mice, etc.) [34]. In my prior publication, I first proposed that cellular stress-induced AMPK activation is critical for facilitation of hippocampal long-term potentiation (LTP), considered a cellular correlate for learning and memory [5]. Indeed, AMPK has been found localized in hippocampal CA1 pyramidal neurons and glutamate, NMDA, potassium chloride, and high frequency stimulation have been shown to induce AMPK activation in cortical and hippocampal neurons [7,35,36]. Although an increase in Ca2+ levels is critical for neuronal activation and LTP induction, inhibition of ROS significantly inhibits hippocampal CA1 LTP, indicating that cellular stress-induced AMPK activation may play a pivotal role in neuronal excitation [37-40].

In my most recent publication, I noted that forskolin activates both AMPK and the transposable element syncytin-1 (necessary for human placental formation), increases human oocyte fertilization rates when combined with the AMPK activator cilostamide, and promotes chemically-induced LTP in hippocampal slices [6,26,41-44]. Transposable elements (TEs) are found in human oocytes, human sperm, and in human neural progenitor cells within the hippocampus [45-48]. TEs are also activated and can be induced to transpose or “jump” from one genomic location to another by increases in Ca2+ or ROS [49-51]. Exercise was shown to enhance LINE-1 (L1) retrotransposition (a TE of the retrotransposon class) in the dentate gyrus of the hippocampus in mice and L1 expression and retrotransposition in the adult mouse hippocampus was reported to enable long-term memory formation [52,53]. Because forskolin and caffeine, both of which activate AMPK, have recently been shown to promote accelerated emergence from anesthesia in rats and caffeine activates both mouse oocytes (models for human oocytes) and TEs, I proposed that cellular stress-induced AMPK activation may represent a common mechanism linking consciousness with learning, memory, and the creation of human life [25,26,33,54,55].

A primary cellular target of hypnotic agents (e.g. propofol) used for the induction and maintenance of general anesthesia is the GABAA receptor [66]. The GABAA receptor is located throughout the brain (cortex, thalamus, brain stem, and striatum) and binding of propofol post-synaptically to GABAA receptors enhances neural inhibition by the primary inhibitory neurotransmitter GABA, contributing to a loss of consciousness [66]. Interestingly, the GABAA receptor antagonist bicuculline, which reverses propofol anesthesia, activates AMPK in mouse cortical neurons via Ca2+ influx and flumazenil (a GABAA receptor antagonist) induces preconditioning by increasing the levels of ROS [56-58].  Basheer et al. as well as researchers from the University of Pennsylvania showed that AMPK is activated during extended periods of wakefulness but is inhibited during sleep in the basal forebrain and cerebral cortex of rats and mice [59,60]. Decreases in AMPK activation during sleep were also associated with increases in ATP, which would decrease AMPK activation as increases in the AMP(ADP)/ATP ratio activates AMPK [34,59]. Creatine, which also activates AMPK, decreased total sleep time, NREM sleep, and NREM delta activity significantly in rats [61,62]. Combined use of the anesthetic agents ketamine and xylazine in rats also led to an ATP increase that positively and significantly correlated with EEG delta activity [63]. However, the sedative and α2-receptor agonist clonidine activates AMPK in mice and xylazine, an analog of clonidine, activates AMPK in the rat cerebral cortex, hippocampus, thalamus, and cerebellum, provocatively indicating that low-dose anesthetic administration may actually promote wakefulness, arousal, and consciousness through activation of AMPK [64,65].

Low dose anesthetic-induced AMPK activation may also explain the phenomenon of paradoxical excitation. Curiously, low doses of nearly every anesthetic drug have been shown to induce paradoxical excitation [66]. As the name implies, before inducing unconsciousness, general anesthetic administration may result in a temporary increase in neuronal excitation, characterized by an increase in beta activity on the electroencephalogram (EEG) and eccentric body movements [66,109]. Because AMPK is activated by cellular stress induction (ROS, Ca2+, AMP(ADP)/ATP ratio increase) and because ROS and Ca2+ increases are critical for activation of pyramidal neurons, it is likely that many anesthetics induce rapid neuronal activation and paradoxical excitation in low doses by promoting cellular stress-induced AMPK activation [34,37-40]. Indeed, propofol, one of the most commonly-used anesthetics to induce and maintain general anesthesia, activates AMPK via an increase in ROS and Ca2+, promotes hippocampal neural stem cell differentiation, and promotes neuronal viability [67-69]. Sevoflurane, a commonly-used inhaled anesthetic, activates AMPK via an increase in ROS, increases Ca2+ levels in mouse brain cells, and enhances memory in rats at low doses [70-72]. Ketamine also activates Ca2+ channels in rat cortical neurons, increases ROS levels in the brain of rats, enhances hippocampal CA1 LTP in rats, and also functions as an antidepressant by activating AMPK in the rat hippocampus in vivo [73-76]. Prominent beta activity on the EEG has also been observed just before return of consciousness in healthy adult volunteers anaesthetized with propofol or sevoflurane (similar to paradoxical excitation), suggesting that the decrease of an anesthetic to a low, stimulatory level after removal of anesthesia may explain the increase in beta activity just before return of consciousness as well as during paradoxical excitation [6,66,77]. Hence, low dose anesthetic-induced AMPK activation may potentially accelerate emergence from anesthesia as well as promote beneficial arousal in disorders of consciousness (e.g. minimally conscious state, persistent vegetative state, coma, etc.) [6].

As noted above, nearly every neurotransmitter that plays a critical role in promoting wakefulness, arousal, and consciousness activates AMPK (glutamate, acetylcholine, orexin, histamine, norepinephrine, dopamine, and serotonin) and commonly used drugs that induce and maintain general anesthesia also activate AMPK in low doses (propofol, sevoflurane, isoflurane, ketamine, dexmedetomidine, and midazolam) [7-23]. Compounds that have recently been shown to accelerate emergence from anesthesia also activate AMPK (carbachol, orexin-A, histamine, dopamine, dopamine D1 receptor agonists, nicotine, caffeine, and forskolin) [9-11,13,24-33]. Additionally, a recent study by Hambrecht-Wiedbusch et al. strikingly demonstrated that although sub-anesthetic doses of ketamine increased anesthetic depth and induced burst suppression during isoflurane anesthesia, ketamine paradoxically accelerated recovery of consciousness in rats [78]. Such evidence supports the notion that while larger doses of anesthetics are effective at inducing loss of consciousness, low-dose anesthetic administration may facilitate rapid, cellular stress-induced neuronal activation that is mediated by AMPK activation [6].

Although they do not have a nervous system, plants produce nearly every neurotransmitter that promotes wakefulness, arousal, and consciousness in humans, including glutamate, acetylcholine, histamine, norepinephrine, dopamine, and serotonin [79-82]. The production of these neurotransmitters in plants is often associated with the induction of cellular stress (i.e. via wounding, osmotic stress, etc.) and partly serves as a defense mechanism [79-82]. Fungal infection of certain rice cultivars for example increases the production of serotonin, which suppresses leaf damage and reduces biotic stress [83]. ROS and Ca2+ also play critical roles in the production of secondary metabolites, compounds that plants produce partly for the purpose of self defense [84,85]. Interestingly, several abiotic stressors including nutrient deficiency, salt, osmotic, oxidative, and ER stress activates autophagy in Arabidopsis in a SnRK1-dependent manner. SnRK1 is the plant ortholog of AMPK [86]. Such evidence suggests that a mechanism of cellular stress-induced AMPK activation by neurotransmitters may have been evolutionarily conserved to promote neuronal activation in the human brain.

Indeed, the well-studied AMPK activator metformin activates AMPK in hippocampal neurons in vivo and enhances neurogenesis in the subventricular zone and the subgranular zone of the dentate gyrus, indicating that metformin may enhance brain repair and recovery of consciousness in disorders of consciousness [24,87,88]. Metformin also alleviates accelerated cellular aging defects and activates AMPK in Hutchinson-Gilford progeria syndrome (HGPS), a genetic disorder characterized by an accelerated aging phenotype caused by faulty splicing of the LMNA gene that also occurs in normal human cells at low levels [1,89,90]. Interestingly, temsirolimus (an analog of the macrolide rapamycin), alleviates accelerated aging defects in HGPS cells but increases the levels of ROS in both normal and HGPS cells within the first hour of treatment [91]. Metformin also activates the telomere-lengthening enzyme telomerase (which is derived from a transposable element) in an AMPK-dependent manner [92]. Cellular stress and AMPK activation also promotes oocyte maturation (precedes and is critical for oocyte activation), the acrosome reaction in human sperm (necessary for oocyte penetration and fertilization), and human placental development [26,93-95]. Forskolin and caffeine also induce the acrosome reaction in human sperm [96,110].

Lastly, increases in ROS, Ca2+, and AMPK activation are also critical for T cell activation and hence latent HIV-1 reactivation, a method currently pursued by HIV-1 cure researchers to reactivate dormant HIV-1 residing in T cells to facilitate virus detection and destruction by the immune system (called the “shock and kill” approach) [5,97-101]. Strikingly, forskolin reactivates latent HIV-1 in human U1 cells, a myelo-monocytic cell line used as a model for HIV-1 latency [102]. Early data has also demonstrated that metformin destabilized the latent HIV-1 reservoir in patients chronically infected with HIV-1 and significantly reduced cellular markers positively associated with T cells latently infected with HIV-1 [103,104]. Such evidence provides a compelling indication that cellular stress-induced AMPK activation links transposable elements and alleviation of accelerated cellular aging with potential HIV-1 eradication, consciousness, and the creation of human life, all hypotheses that I originally proposed [1-6].

https://www.linkedin.com/pulse/metformin-shares-common-mechanism-nearly-every-drug-ampk-finley/

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