Hey Blogger Fam, check out my latest post when you
have a minute. The post basically explains why some children with Autism get
better temporarily (i.e. improvement in speech, decrease in repetitive
behaviors) when they get a fever. Also
known as the “fever effect”, this is basically another rendition of the “shock
and live” approach, in which the induction of mild stress to a cell, in this
case heat stress, leads to the activation of the master metabolic regulator
AMPK and a beneficial cellular response.
The child’s behavior improves because mild heat stress or a “shock” to
neurons of the brain causes those brain cells to do what they were designed to
do that much better. The broccoli sprout
compound sulforaphane, which activates AMPK, also activates the heat shock
response and has shown efficacious results in patients with autism and also
improves accelerated aging defects in skin cells taken from progeria
patients. How is this possible? Is the
correct functioning of neurons related to slowing or reversing accelerated
aging defects? Indeed it is. Heat
stress, which has been shown in independent studies to activate AMPK, is yet an
additional term that equates to “what doesn’t kill you makes you stronger”. Heat stress, hyperthermia, or the activation
of heat shock proteins have been shown to promote T cell functionality, wake up
dormant HIV-1 viruses so that the immune system can detect and kill it, promote
the maturation of oocytes in preparation for artificial oocyte activation or
activation by sperm, promote the induction of the acrosome reaction in sperm (a
process necessary for oocyte penetration), promote “activation” and killing of
cancer stem cells, promote the develop of embryonic stem cells into cells that
will eventually make up the body of the baby, and enhance learning and memory
in the brain. The fancy term to describe
the process that enhances learning and memory is called long-term potentiation,
which basically involves a strengthening in connections between neurons if they
are continuously challenged. Heat stress, an intellectually stimulating
environment, exercise, and countless naturally-occurring compounds all enhance
long-term potentiation, learning and memory, and activate AMPK. Interestingly,
high-frequency stimulation and deep brain stimulation also activate AMPK in
neurons and improve neurological symptoms, indicating that mild transient
electrical pulses are another form of stress.
Lastly, a stark example of how heat stress and learning and memory in
neurons are connected to the creation of human life involves a heat-sensitive
channel called TRPV3. Mild heat stress and a compound from oregano (called
carvacrol) activates this channel. This
channel is also present in the brain and in oocytes. If you knock this channel out in the brain,
long-term potentiation and learning and memory are impaired. However, if you activate this channel on
oocytes with the oregano compound, the oocyte will become activated as if it
had been fertilized by sperm (called parthenogenesis). Again, heat stress and compounds that induce
mild stress promotes a compensatory and beneficial response from a cell. This
response is orchestrated by AMPK activation and results in a “shock to live”
(e.g. oocyte maturation/activation, stem cell “activation”, learning and memory
in the brain, sperm capacitation/acrosome reaction) or a “shock to kill” (e.g. latent
HIV-1 reactivation, cancer stem cell “activation” and/or cell death).
AMPK links beneficial
responses to the “Fever Effect” in Autism with Progeria, HIV-1 latency, &
Oocyte activation: The "Shock and Live" approach
In line with recent findings demonstrating that sulforaphane, an isothiocyanate heavily concentrated in broccoli sprouts, significantly ameliorated accelerated aging defects in cells derived from patients diagnosed with Hutchinson-Gilford progeria syndrome (HGPS), a recently completed placebo-controlled, double-blind, randomized trial by researchers from Harvard Medical School, The Johns Hopkins University School of Medicine, and University of Massachusetts Medical School demonstrated that participants diagnosed with moderate to severe Autism Spectrum Disorder (ASD) who received sulforaphane showed substantial and significant improvements in behavior, social interaction, and verbal communication compared to participants assigned to placebo [1,2]. Discontinuation of sulforaphane also led to a reversal of these improvements, mirroring levels obtained before initiation of treatment [2].
Interestingly, parents and clinicians, over the past few decades, have reported noticeable improvements in behavior in children with ASD during or after the onset of febrile illness (i.e. fever). Also known as the “fever effect”, transient increases in body temperature may positively influence neuronal and synaptic function in the brain of ASD patients, an effect that appears to be at least partially mimicked by sulforaphane. As described below, because sulforaphane and other compounds regulate proteins that are critical for the induction of the heat shock response and because heat shock proteins also play critical roles in the reactivation of latent HIV-1, oocyte maturation, sperm capacitation/acrosome reaction, the promotion of learning and memory in the brain, and differentiation of adult stem cells, the “fever effect” likely represents a “shock” or the induction of cellular stress, leading to the activation of the master metabolic regulator AMPK, resulting in a beneficial cellular stress response. The response to this stressor generates a cell-specific “shock to live” (e.g. oocyte maturation/activation, stem cell differentiation, stimulation of learning and memory, sperm capacitation/acrosome reaction) or a “shock to kill” (e.g. latent HIV-1 reactivation, cancer stem cell differentiation and/or cell death).
ASD, a neuro-developmental disorder that disproportionately affects males, is characterized by repetitive or compulsive behaviors, impairments in social development, and deficiencies in verbal and non-verbal communication that are often observable within the first two years of life. Causes underlying ASD also appear to be multi-factorial, with interactions between environmental factors and genetics leading to deleterious alterations in neuronal network functionality and immune system regulation [3-5]. As noted above, anecdotes and case reports have indicated that amelioration of symptoms associated with ASD are positively correlated with the onset of febrile illness. A particularly interesting example of the “fever effect” in ASD occurred at New York University’s Bellevue Psychiatric Hospital, in which improvement in concentration and social interactions were noted in children with temperatures between 38.9 to 40.6°C, due to an outbreak of viral upper respiratory tract infections [6-8]. Indeed, a prospective study of 30 children with ASD during and after febrile illness (body temperature greater than or equal to 38.0°C) revealed that compared to afebrile ASD patients, fewer aberrant behaviors for febrile ASD patients were recorded on the Aberrant Behavior Checklist subscales of irritability, hyperactivity, stereotypy (i.e. persistent repetition of an act), and inappropriate speech, indicating a transient enhancement or correction of neuronal functioning in response to fever onset [8].
Because sulforaphane has been shown to transiently induce cellular stress, resulting in the upregulation of the master antioxidant transcription factor Nrf2 and activation of AMPK (which activates Nrf2), febrile illness likely induces a transient induction of cellular stress (i.e. “heat shock”), resulting in a compensatory and beneficial upregulation of cellular factors that enhance or promote neuronal functioning [9,10,11]. Indeed, Singh et al. recently demonstrated in a placebo-controlled, double-blind, randomized trial that patients receiving sulforaphane showed significant behavior improvements as measured by the Aberrant Behavior Checklist and the Social Responsiveness Scale compared to patients receiving placebo [2]. Patients who received sulforaphane also experienced improvements in social interaction, abnormal behavior, and verbal communication on the Clinical Global Impression Improvement Scale [2].
Because sulforaphane induces cellular stress via an increase in stressors including reactive oxygen species (ROS) and because febrile illness represents the induction of cellular stress, the beneficial effects of sulforaphane demonstrated in ASD patients suggests that sulforaphane may also induce cellular stress and a beneficial cellular response by activating or upregulating mediators that promote the heat shock response. Heat shock consists of subjecting a cell to a higher temperature than the ideal body temperature of an organism. The heat shock response is a cellular response to heat shock that induces the activation of heat shock factor-1 (HSF1), the major regulator of heat shock protein (HSP) transcription, and the upregulation of HSPs that aid in repairing or targeting misfolded proteins for degradation [12]. Interestingly, HSPs also respond to other forms of cellular stress, including ROS and intracellular calcium (Ca2+) increases, both of which also activate AMPK [13-15]. Interestingly, sulforaphane has been shown to induce a significant and rapid HSF1 mediated heat shock response and heat stress has also been shown to increase ROS production, promoting nuclear translocation of Nrf2 and upregulation of Nrf2 target genes [16,17]. Furthermore, as sulforaphane activates AMPK and AMPK activates Nrf2, heat stress has also been shown to activate AMPK, promoting insulin-independent glucose transport in muscle cells and the killing of breast and pancreatic cancer stem cells [18,19]. HSP90 has also been to found to interact with and maintain AMPK activity, providing further evidence that the induction of heat shock likely leads to activation of AMPK and a beneficial cellular response [53].
Interestingly, as sulforaphane has been shown to activate both AMPK and Nrf2 and significantly ameliorate accelerated aging defects associated with Hutchinson-Gilford progeria syndrome (HGPS) (which is associated with dysfunctional Nrf2 signaling), other AMPK-activating compounds that have demonstrated efficacious results in HGPS may also be expected to induce certain mediators constituting the heat shock response [1]. Indeed, the proteasome inhibitor MG132, the macrolide rapamycin, and vitamin D have each been shown to improve symptoms of accelerated aging in HGPS fibroblasts, activate HSF1 or increase HSP expression, and activate AMPK, indicating that chemically distinct compounds including sulforaphane, MG132, rapamycin, and vitamin D likely induce cellular stress, leading to the activation of AMPK and a beneficial cellular response in diseases as disparate as HGPS and ASD [20-28].
As febrile illness and the induction of the heat shock response have been shown to mitigate irritability, hyperactivity, stereotypy, and inappropriate speech in ASD patients, it would be expected that the application of heat stress or the induction of mediators of the heat shock response would also enhance or improve certain aspects of neuronal functionality. Indeed, heat stress alone and heat stress preconditioning before diffuse axonal injury led to higher expression levels of HSP70 and a significant improvement in the Morris Water Maze task (a behavioral procedure used to study spatial learning and memory) and long-term potentiation (LTP) in rats compared with diffuse axonal injury alone [29]. LTP is characterized by a “persistent increase in synaptic strength following high-frequency stimulation” and is often studied in pyramidal neurons of the hippocampus, an area of the brain important for learning and memory [30]. Interestingly, neuronal depolarization (i.e. activation) has been shown to activate HSF1, heat shock has been shown to improve synaptic integrity and memory consolidation, and HSF1 agonists (e.g. exercise) have been shown to improve cognition in models of dementia [31]. A recent study by Notenboom et al. also showed that prolonged hyperthermia in rats enhanced hippocampal CA1 long-term potentiation and sprouting of mossy fiber collaterals into the dentate gyrus [32]. Perhaps most proactively, however, is a recent study by Brown et al. demonstrating that high-frequency stimulation-induced LTP was attenuated at CA3-CA1 pyramidal cell synapses in hippocampal slices from Trpv1 and Trpv3 knockout (KO) mice [33].
Interestingly, carvacrol, a monoterpenoid phenol found in the essential oil of Origanum vulgare (oregano), is a potent activator of the transient receptor potential cation channel, subfamily V, member 3 (TRPV3), a nonselective cation channel that functions in vasoregulation and temperature sensation and is activated between the temperatures of 22 and 40 degrees Celsius [34,35]. The TRPV3 channel has also been shown to associate with and form heteromeric channels with the Ca2+-permeable TRPV1 channel, another nonselective cation channel that is also regulated by temperature sensation and is activated by both physical and chemical stimuli, including temperatures greater than 43 degrees Celsius as well as the natural compound capsaicin (an active component of chili peppers from the genus Capsicum) [35-37]. As both carvacrol and capsaicin have been shown to activate AMPK and heat stress has been shown to both enhance hippocampal LTP and activate AMPK, AMPK activation likely represents a common mechanism of action explaining the therapeutic actions of several chemically distinct compounds and methodologies in the promotion of synaptic plasticity and LTP [38,39]. Indeed, a recent study demonstrated that high frequency stimulation of hippocampal neurons in the dentate gyrus activates AMPK and induces early-phase long-term potentiation (E-LTP) in vivo in rats [40]. E-LTP was prevented by pharmacological inhibition of AMPK, highlighting a critical role for AMPK in learning and memory [40]. High frequency deep brain stimulation of the lateral habenula (an area of the brain that plays an important role in emotion, motivation, and reward) has also been shown to activate AMPK, facilitating antidepressant actions in an animal model of tricyclic antidepressant resistance [41]. Resveratrol, a phytoalexin found in grapes and red wine, has also been shown to rapidly increase protein levels and synaptic accumulation of the AMPA receptor and increase the strength of excitatory synaptic transmission in rat primary neurons via AMPK activation [42]. Because AMPA receptors mediate fast excitatory transmission and are essential for the induction of LTP and synaptic plasticity, AMPK activation likely represents a central node underlying the beneficial effects of heat stress and compounds such as sulforaphane in ameliorating neuro-developmental effects associated ASD.
Interestingly, because knockdown of TRPV3 channels (channels that are activated in response to mild temperature elevations and by compounds including carvacrol) attenuates LTP in hippocampal pyramidal neurons and because TRPV3 channels are also located on oocytes, it would be expected that mild and transient heat stress would enhance or promote oocyte maturation and/or activation. Indeed, AMPK activation has been consistently shown to play a critical role in the induction of oocyte meiotic resumption and maturation in preparation for oocyte activation and heat stress has also been shown to stimulate oocyte meiotic resumption and maturation in an AMPK-dependent manner [43, 44]. Intriguingly, the proteasome inhibitor MG132 and methylene blue have both been shown to activate AMPK, alleviate accelerated aging defects in fibroblasts derived from Hutchinson-Gilford progeria syndrome (HGPS) patients, and stimulate oocyte meiotic resumption, providing compelling evidence that AMPK activation represents a central node linking the therapeutic effects of chemically distinct compounds that facilitate the creation of human life [20,27,45-48].
Furthermore, Carvacho et al. demonstrated that the TRPV3 channel is differentially expressed in mouse oocytes during maturation and reaches peak density and activity at metaphase II, the stage at which oocytes develop the competency to initiate Ca2+ oscillations in response to fertilization [49]. The authors also showed that strontium chloride (SrCl2), a compound that induces parthenogenetic activation of mammalian oocytes and has resulted in successful term pregnancies and the birth of normal children, promotes Ca2+ oscillations and induces oocyte activation via TRPV3-mediated Sr2+ influx, as TRPV3 deletion in oocytes (TrpV3−/−) failed to respond to Sr2+-induced activation [49,50]. As the TRPV3 channel is Ca2+ permeable and SrCl2-induced oocyte activation is thought to occur via mimicking Ca2+ by sensitizing and potentiating IP3 receptors, the authors also showed that application of the TRPV3 agonist carvacrol in heterozygous oocytes (TrpV3+/−) led to a substantial increase in intracellular Ca2+ levels as well as parthenogenesis in both TrpV3+/− and wild-type oocytes (TrpV3+/+) (as measured by pronuclear formation and cleavage to the 2-cell stage), whereas TRPV3-deficient oocytes failed to respond [49]. Because TRPV3 channels are also critical for hippocampal LTP in the brain and because the TRPV3 channel agonist carvacrol activates AMPK and AMPK activation is essential for the induction of hippocampal LTP, activation of AMPK is likely critical for the creation of all human life (via oocyte activation) and for the processes of learning and memory formation [51].
Interestingly, recent studies have also demonstrated that knockout of HSF1 in oocytes leads to depletion of HSP90alpha, delayed meiotic resumption, and defective asymmetrical division [52]. As HSP90 has been shown to interact with and maintain AMPK activity and AMPK activation is essential for efficient T cell activation, heat stress or the induction of mediators of the heat shock response would be expected to promote the reactivation of latent HIV-1 in CD4+ memory T cells via low-level T cell activation, a method known as the “shock and kill” approach [51,53]. T cell activation-induced latent HIV-1 reactivation will likely facilitate destruction of the virus through immune-system detection or via virus-induced destruction of the host cell [51]. Indeed, recent studies have demonstrated that T cell activation at fever temperatures (39.5°C) activates HSF1 and HSF1 is essential for T cell proliferation in vitro [54,55]. Also, knockdown of AMPK and CaMKK2 (an upstream activator of AMPK) has been shown to significantly inhibit HIV-1 replication [56]. Strikingly, Roesch et al. showed that HIV-1 replication was increased 2 to 7 fold by culturing primary CD4+ T lymphocytes at a fever-like temperature (39.5°C) and that hyperthermia enhanced HIV-1 reactivation in a model of latently-infected cells in a HSP90-dependent manner [57]. Several recent studies have also demonstrated that HSP90 promotes HIV-1 reactivation from latency in CD4+ T cells by enhancing the activity of host cell several transcription factors (NF-κB, NFAT, and STAT5) that are critical for both T cell activation and HIV-1 reactivation and replication [58,59]. Particularly compelling is a recent study by Pan et al. showing that HSF1 participates in HIV-1 transcription and is essential for latent HIV-1 reactivation by binding to the HIV 5'-long terminal repeat (LTR) to reactivate viral transcription [60]. Overexpression of HSF1 improved HIV transcription whereas knockout of HSF1 inhibited HIV transcription [60]. Interestingly, in this same study, resveratrol, MG132, and hemin (an iron-containing porphyrin) were also shown to reactivate latent HIV-1 in a T cell line [60]. Similar to resveratrol and MG132, hemin has also been shown to activate AMPK, again placing AMPK activation as a centerpiece facilitating the reactivation of latent HIV-1, oocyte meiotic induction and activation, and learning and memory formation induced by LTP [61].
Activation of mediators of the heat shock response may also play critical roles in other physiological processes that are essential for the creation and the beginnings of human life. As noted above, in addition to heat stress, HSPs also respond to other forms of cellular stress, including ROS and intracellular Ca2+ increases, both of which activate AMPK [13-15]. Additionally, HSP90 has been found to localize in the neck, midpiece, and tail regions of human sperm and HSP90 inhibition significantly decreases intracellular Ca2+ concentrations during capacitation, a process that is essential for oocyte fertilization [62]. Indeed, an increase in the levels of intracellular Ca2+ is critical for the initiation of the acrosome reaction in sperm, a process that facilitates sperm penetration of the oocyte and is thus indispensable for fertilization. Interestingly, ROS and vitamin D, both of which activate AMPK, have each been shown to induce the acrosome reaction in sperm, indicating that induction of cellular stress is critical for the promotion of the acrosome reaction in sperm, facilitating the creation of human life [15,28,63,64]. Vitamin D has also been shown to improve accelerated cellular aging defects in progeria, indicating that the creation of human life and the amelioration of symptoms of accelerated aging may depend on the induction of a cellular stress response [22]. Heat stress has also been shown to promote the differentiation of human adult stem cells and AMPK activation has also recently been shown to be critical in embryonic development by facilitating the differentiation of mouse embryonic stem cells into endoderm, again indicating that AMPK activation is critical, if not indispensable, for the creation and beginnings of life [65,66,67].
In conclusion, the evidence presented above strongly supports the provocative implication that the induction of cellular stress, mediated by heat, ROS, intracellular Ca2+ increases, an AMP/ATP ratio increase, etc. leads to a beneficial compensatory cellular response. The induction of this cellular response and subsequent activation of AMPK by chemically distinct compounds including sulforaphane, MG132, vitamin D, rapamycin, methylene blue, carvacrol, and likely many others indicates that cellular stress-induced AMPK activation may represent a central node in the amelioration of disease and the creation of human life. Indeed, cell and context-specific AMPK activation may induce a “shock to live” (e.g. oocyte maturation/activation, stem cell differentiation, learning and memory in the brain, sperm capacitation/acrosome reaction) or a “shock to kill” (e.g. latent HIV-1 reactivation, cancer stem cell differentiation and/or cell death).
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