By ISAF Headquarters Public Affairs Office (originally
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(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
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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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