Tuesday, December 6, 2016

C-fos at night

Being exposed to light during what should be our "night" appears to elevate c-fos levels in the mammalian brain, per a 1990 study:
Photic information entrains a circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the mammalian hypothalamus to environmental light/dark cycles. To determine whether light regulates c-fos gene expression in the SCN, we have measured c-fos mRNA levels in the SCN of the golden hamster. We report that, during the subjective night, light causes a rapid increase in levels of c-fos mRNA in the SCN. Light pulses of 5 min duration are sufficient to induce c-fos mRNA, and the highest mRNA levels occur 30 min following the onset of light. The minimum level of illumination required to induce an increase in c-fos mRNA is indistinguishable from the minimum irradiance that produces a phase shift in the hamster's circadian rhythm of activity. In addition, the induction of c-fos mRNA in the SCN by light is itself under circadian regulation. Light induction of c-fos mRNA occurs only during the subjective night, at circadian times when photic phase shifting of activity occurs. Taken together, these data suggest that c-fos may be a molecular component of the photic pathway for entrainment of mammalian circadian rhythms.

https://www.ncbi.nlm.nih.gov/pubmed/2116813

If elevated c-fos is connected to the creation of addictive neural assemblies in the brain (briefly discussed in the preceding post), then being exposed to light during what should be our sleeping period might increase the possibility of becoming addicted to whatever pleasurable thing we are doing while up at night.

Why do casinos keep the lights on constantly? Is it just so that casino patrons don't notice how much time they've been inside gambling, or have the casinos observed an increase in gambling addiction-like behavior as a result of their exposing their patrons to light when the patrons ought to be in bed?

Why are night owls more prone to addictive disorders than early risers? (https://www.ncbi.nlm.nih.gov/pubmed/26250146) Is it because they are engaged in their addictions when their bodies should be asleep?

Being an evening person, rather than a morning person, was recently found to be linked to a higher risk of becoming addicted to smartphones in German adolescents. (https://www.ncbi.nlm.nih.gov/pubmed/27499228) Is that because the evening people are more likely to have a smartphone shining in their faces when they should be asleep?

All very interesting. It almost makes me want to go to bed earlier. Actually, why don't I? I can read in the early morning just as easily as in the late evening. Perhaps it's time to make my bedtime firm.

Wednesday, November 30, 2016

Up c-fos to increase brain learning/unlearning?

C-fos increases in the brain right after administration of drugs such as cocaine (http://www.pnas.org/content/87/17/6912.full.pdf), and it appears to be elevated in some brain areas when the brain is "unlearning" a previous memory pattern, such as in this study looking at c-fos levels in rats just after they brought about extinction of a previously-reinforced behavior (i.e., it's as though they stopped feeding Pavlov's dog after ringing bells, observed how long it took for the dog to stop salivating after bell ringing, then examined the dog's brain tissue) (https://www.ncbi.nlm.nih.gov/pubmed/24315832):
Taking into account that c-Fos activity reflects the last part of this process of extinction in this study, we cannot preclude the possibility of a new inhibitory learning taking place at the time. According to some authors, the extinguished memory is not erased but inhibited, so that the observed c-Fos changes may reflect this new learning process that could be occurring at the end of the extinction procedure.

Researchers seem reluctant to say that c-fos is a causative part of making the neuronal assemblies associated with addiction, but they do find a strong correlational link:
The described neurochemical and molecular biological mechanisms all support the idea that c-fos promoter activation is an indicator of strong and persistent calcium influx into synapses of MSNs that received the most excitatory glutamatergic input. Drug-induced dopamine can synergistically enhance c-fos promoter activation in these strongly activated MSNs. It should be noted that a lack of Fos expression in a neuron does not imply a complete lack of neural activity, only that it is not depolarized strongly or persistently enough to produce enough intracellular calcium to activate the ERK signaling pathway. The earlier section describing in vivo electrophysiology and cellular imaging studies indicate that the neurons receiving the most excitatory glutamatergic input are determined by the context and cues present during drug administration. Altogether these data support the hypothesis that Fos-expressing neurons in corticostriatal circuitry can act together as a unit to form neuronal ensembles that encode and mediate conditioned drug behaviors. It is important to note that we treat c-fos and Fos only as markers of activated neurons in this hypothesis and do not imply that these molecules are directly involved in neuronal ensemble function. 

Suppose someone wants to learn a new behavior or lessen the pull of a learned, unhelpful behavior. Might it be helpful to increase c-fos somehow during the learning/unlearning period? Delta-fosB, which I discussed in previous posts, accumulates in addiction and represses c-fos, which repression could be preventing addiction-breaking learning/unlearning. That gives support to the idea that not increasing c-fos is unhelpful when overcoming an addiction. But it does not logically follow that increasing c-fos will therefore be helpful in overcoming an addiction. I'll have to look and see if there are studies done specifically on that.

There are studies that look at how to increase c-fos expression. Three tested ways to increase c-fos expression are forskolin (an herbal supplement already in use by some as a weight loss help), BDNF (brain-derived neurotrophic factor, a protein), and membrane depolarization (brought about via neurotransmitters or KCl) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696896/). BDNF is being looked at as a possible aid in cocaine addiction (https://www.ncbi.nlm.nih.gov/pubmed/26923993), and forskolin seems able to induce a strengthening of synapses involved in memory formation (but the effect is much smaller in older rat brain tissue--https://www.ncbi.nlm.nih.gov/pubmed/15911893). Glutamate is a neurotransmitter, and monosodium glutamate (MSG) is known to evoke c-fos activity (https://www.ncbi.nlm.nih.gov/pubmed/26762887); a quick Google search finds that many people feel MSG is addictive for them, for what that's worth.

Here's a fun idea to test whether upping c-fos helps develop new brain pathways associated with memory and addiction. Try a new activity that you would like to become slightly addicted to, and eat Nacho Cheese Doritos while you do it.  Nacho Cheese Doritos are a good source of MSG. Then see if you are more fixated on the new activity afterward than you would have expected. Even if the experiment bombs, you'll have gotten to eat Doritos in the name of science!

Monday, November 21, 2016

C-fos, addiction, and eros

Another molecule connected to addiction is c-fos (https://en.wikipedia.org/wiki/C-Fos), production of which is increased after using cocaine, methamphetamine (https://www.ncbi.nlm.nih.gov/pubmed/2118661), and other such drugs and possibly after mating (c-fos increases have been found in rats after mating--https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834303/). Various articles in the past few years have claimed that falling in love is the same to the brain as getting high on crack cocaine (e.g., http://www.salon.com/2015/02/14/love_is_like_cocaine_the_remarkable_terrifying_neuroscience_of_romance/, https://www.psychologytoday.com/blog/the-joint-adventures-well-educated-couples/201208/falling-in-love-is-smoking-crack-cocaine, http://www.medicaldaily.com/oxytocin-love-hormone-fuels-romance-how-your-brain-works-when-youre-love-269067). How very unromantic.

C-fos appears to be important in effectuating morphological changes in the brain (specifically, increased dendritic branching and dendritic spine density) as the process of addiction occurs, as well as in overcoming addiction after the object of the addiction has been removed (http://www.jneurosci.org/content/26/51/13287.full).

In a recent post, I cited a paper indicating that an accumulation of ΔFosB can be considered the molecular "on-switch" of addiction in the brain. A 2008 rat study found that ΔFosB represses c-fos (http://www.jneurosci.org/content/28/29/7344.full). Anhedonia--an inability to experience pleasure from positive life events--is more common in psychoactive substance-using populations, and it lessens as they get off drugs (https://www.ncbi.nlm.nih.gov/pubmed/24270310). It appears as though the brain could be homeostatically acting to remain "faithful" to the source of pleasure it became addicted to and so represses c-fos production that would allow formation of competing neural pathways associated with other pleasures. That would help explain the inability to find much pleasure outside of one's addiction and perhaps the occurrence of monogamy. Again, very unromantic.

I feel like I should repost this all on February 14th to be contrary. "Your mate might be faithful to you just because of an accumulation of ΔFosB that prevents him/her from finding the same pleasure with someone else." That won't show up on a Hallmark card anytime soon.... Still, you might as well face it if you are indeed addicted to love.



Saturday, November 19, 2016

Ellagic acid apparently helps with withdrawal symptoms from morphine, too

Last time I posted about ellagic acid possibly being a help to overcome addiction. Afterwards, I came across this study from two years ago finding that it helped alleviate morphine withdrawal symptoms:
Abstract
According to our previous study, ellagic acid has both dose-related central and peripheral antinociceptive effect through the opioidergic and l-arginine-NO-cGMP-ATP sensitive K+channel pathways. In the present study, the systemic antinociceptive effects of ellagic acid in animal models of pain, and functional interactions between ellagic acid and morphine in terms of analgesia, tolerance and dependence were investigated. Ellagic acid (1–30 mg/kg; i.p.) showed significant and dose-dependent antinociceptive effects in the acetic acid-induced writhing test. Intraperitoneal ellagic acid acutely interacted with morphine analgesia in a synergistic manner in this assay. Ellagic acid (1–10 mg/kg; i.p.) also exerted analgesic activity in the hot-plate test. Pre-treatment with naloxone (1 mg/kg; i.p.) significantly reversed ellagic acid, morphine as well as ellagic acid-morphine combination-induced antinociceptin in these two tests. More importantly, when co-administered with morphine, ellagic acid (1–10 mg/kg) effectively blocked the development of tolerance to morphine analgesia in the hot-plate test.
Likewise, ellagic acid dose-dependently prevented naloxone-precipitated withdrawal signs including jumping and weight loss. Ellagic acid treatment (1–30 mg/kg; i.p.) had no significant effect on the locomotion activity of animals using open-field task. Therefore, these results showed that ellagic acid has notable systemic antinociceptive activity for both tonic and phasic pain models. Altogether, ellagic acid might be used in pain relief alone or in combination with opioid drugs because of enhancing morphine analgesia and preventing morphine-induced tolerance to analgesia and dependence.
http://www.sciencedirect.com/science/article/pii/S0014299914006293

Naloxone (trade name Narcan) causes opioid-withdrawal symptoms in those who are dependent on opioids.

Opiate withdrawal symptoms can be extremely unpleasant:

Early symptoms of withdrawal include:
  • Agitation
  • Anxiety
  • Muscle aches
  • Increased tearing
  • Insomnia
  • Runny nose
  • Sweating
  • Yawning
Late symptoms of withdrawal include:
  • Abdominal cramping
  • Diarrhea
  • Dilated pupils
  • Goose bumps
  • Nausea
  • Vomiting
Opioid withdrawal reactions are very uncomfortable but are not life-threatening. Symptoms usually start within 12 hours of last heroin usage and within 30 hours of last methadone exposure.
http://www.nytimes.com/health/guides/disease/opiate-withdrawal/overview.html

If ellagic acid, a component of easily-obtainable berries and walnuts, can reduce opiate withdrawal symptoms, that seems like something that should become common knowledge, doesn't it? I hope someone tests ellagic acid in humans for relief from opiate addiction withdrawal symptoms.

Tuesday, November 15, 2016

A way to lessen withdrawal anxiety?

In a land of plenty where many cases of cancer and other physical illness have become curable due to medical advances, the problem of intractable mental illness is beginning to be far more apparent. One form of mental disorder that seems to be very prevalent is addictive disorders. One study estimated that approximately half the US population suffers from addictive disorder symptoms in the course of a year:
An increasing number of research studies over the last three decades suggest that a wide range of substance and process addictions may serve similar functions. The current article considers 11 such potential addictions (tobacco, alcohol, illicit drugs, eating, gambling, Internet, love, sex, exercise, work, and shopping), their prevalence, and co-occurrence, based on a systematic review of the literature. Data from 83 studies (each study n = at least 500 subjects) were presented and supplemented with small-scale data. Depending on which assumptions are made, overall 12-month prevalence of an addiction among U.S. adults varies from 15% to 61%. The authors assert that it is most plausible that 47% of the U.S. adult population suffers from maladaptive signs of an addictive disorder over a 12-month period and that it may be useful to think of addictions as due to problems of lifestyle as well as to person-level factors.
http://ehp.sagepub.com/content/34/1/3.short

If nearly half of adults are "addicted" in any given year, then addiction by definition would seem to be a fairly normal process of the brain. When the addiction is to something that helps increase our ability to enjoy and function in life, we call it things like "enthusiasm" or "dedication," but when it robs us of our ability to function productively and healthily, we consider it a disease. (http://www.iflscience.com/health-and-medicine/theres-no-such-thing-as-an-addictive-personality-heres-why/all/) One element of an addictive disorder is that the addicted person suffers from withdrawal symptoms when deprived of the substance or behavior to which he/she is addicted.

What chemically happens in the brain during withdrawal? We know that ΔFosB (delta-FosB), a gene transcription factor is a chemical on-switch for both substance and behavior addictions:
The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor ΔFosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. ΔFosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of ΔFosB occurs after compulsive running, which suggests that ΔFosB may accumulate in response to many types of compulsive behaviors. Importantly, ΔFosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, ΔFosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either ΔFosB or a dominant negative inhibitor of the protein provide direct evidence that ΔFosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that ΔFosB functions as a type of sustained “molecular switch” that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC58680/

When mice are given the opportunity to become addicted to ethanol (alcohol) and then deprived of it, the level of ΔFosB in their brain dramatically rises during the withdrawal period. (http://www.sciencedirect.com/science/article/pii/S0091305713003419) If ΔFosB levels can be kept from rising during the withdrawal period, perhaps that will weaken the power of the addiction and make it easier to get past.

Why does ΔFosB hang around for so long in the brain? Is there a way we can keep it from hanging around for so long so that levels of ΔFosB don't rise as much during withdrawal periods?
The transcription factor ΔFosB (also referred to as FosB2 or FosB[short form]) is an important mediator of the long-term plasticity induced in brain by chronic exposure to several types of psychoactive stimuli, including drugs of abuse, stress, and electroconvulsive seizures. A distinct feature of ΔFosB is that, once induced, it persists in brain for relatively long periods of time in the absence of further stimulation. The mechanisms underlying this apparent stability, however, have remained unknown. Here, we demonstrate that ΔFosB is a relatively stable transcription factor, with a half-life of ∼10 h in cell culture. Furthermore, we show that ΔFosB is a phosphoprotein in brain and that phosphorylation of a highly conserved serine residue (Ser27) in ΔFosB protects it from proteasomal degradation. We provide several lines of evidence suggesting that this phosphorylation is mediated by casein kinase 2. These findings constitute the first evidence that ΔFosB is phosphorylated and demonstrate that phosphorylation contributes to its stability, which is at the core of its ability to mediate long-lasting adaptations in brain.
http://www.jneurosci.org/content/26/19/5131.long

This suggests that inhibiting casein kinase 2 could diminish the amount by which ΔFosB increases in the brain during withdrawal periods. What inhibits casein kinase 2? Two commonly consumed inhibitors of casein kinase 2 are apigenin (highest in chamomile, parsley, and celery) and ellagic acid (highest in berries and walnuts). Chamomile extract containing apigenin has been observed to reduce anxiety (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600408/), and ellagic acid has been observed to lessen withdrawal symptoms in nicotine-addicted mice (https://www.uaeh.edu.mx/investigacion/producto.php?producto=5628).

Therefore, if trying to overcome a behavior that has started to drift into "addiction" territory, I would be sure to include high levels of foods containing ellagic acid and apigenin if I felt anxiety at suspending the behavior to which I'd become addicted. Wild strawberries appear to be one of the very best sources of ellagic acid (http://pub.jki.bund.de/index.php/JABFQ/article/viewFile/3114/3485), which tidbit would no doubt please Ingmar Bergman--a Swedish film producer whose film Wild Strawberries is about a very old man overcoming a lifetime of habitual aloofness--were he still alive.

Monday, November 7, 2016

High altitude link to depression

I live nearly 2000 m above sea level, so I'm especially interested in a finding last year that female mice put in conditions simulating high altitudes are more prone to developing symptoms of depression:

Hypobaric Hypoxia Induces Depression-like Behavior in Female Sprague-Dawley Rats, but not in Males

The researchers housed rats for a week at simulated altitudes of sea level, 10,000 feet and 20,000 feet using altitude chambers, and at local conditions of 4,500 feet, the elevation of Salt Lake City where the research took place. They then used a widely accepted behavioral test in which depression is gauged by how much persistence rodents demonstrate in a swim test. “In female rats, increasing altitude of housing from sea level to 20,000 feet caused a parallel increase in depression-like behavior,” Kanekar says.
The correlation between altitude and high rates of depression and suicide is strikingly obvious in the Intermountain West region of the United States where elevations are considerably higher than in the rest of the country. In 2012, the eight states that comprise the Intermountain West–Utah, Colorado, Wyoming, Montana, Idaho, Nevada, Arizona and New Mexico–had suicide rates exceeding 18 per 100,000 people compared with the national average of 12.5 per 100,000, according to the American Foundation for Suicide Prevention. The high rates of self-inflicted death in the West have earned the region a gloomy moniker: the Suicide Belt.
....
“The fact that both depression and suicide rates increase with altitude implies that current antidepressant treatments are not adequate for those suffering from depression at altitude, leading to high levels of unresolved depression that can contribute to higher levels of suicidal ideation and suicide attempts,” says Kanekar.
http://healthcare.utah.edu/publicaffairs/news/2015/03/03-25-15_KankekarRats.php; full text of study online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376288/.

I know of a couple of people--both of whom are female, which fits the finding of this mice study--dealing with difficult-to-treat depression here in Colorado. (Although most of my regular contacts are LDS, neither of these two people is LDS, which doesn't seem to fit with occasional claims that LDS people are more prone to depression than non-LDS people.) Could their depression be in part due to the lower barometric pressure and oxygen content of Colorado air?

Despite my adoring the mountains, if my daughters were to suffer from chronic depression, I would consider moving to a lower elevation if I couldn't somehow up the amount of oxygen they inhale.

Thursday, November 3, 2016

Learning to conduct

I was asked to be a church choir director a month ago. In my church, we have a lay ministry where we give our time freely in positions as we are called upon to fill them. The choir rehearses most Sundays for about 45 minutes and includes everyone from beginners and children up to very talented instrumental and vocal musicians. And yet, it doesn't actually have many people.

My mother taught me how to wave my hand around in a 4/4 pattern when I was around 11 years old, but she never taught me about ictus, how to bring in singers, or how to cut off a note. She put me in voice lessons with a professional opera singer back when I was in grade school and singing Shirley Temple songs, so I can produce notes well enough. Unfortunately, I am now expected to NOT sing and instead focus on teaching others to sing and directing them appropriately. Thankfully, there are YouTube videos available to help. Here is a good one on ictus, in case you're wondering what that is:


https://www.youtube.com/watch?v=6GmrlY0pA_Q

Wish me luck at this directing gig! (I'm going to need it.)

Thursday, October 27, 2016

Impressive results in overcoming allergies

Yesterday ScienceDaily published a press release about a new technique of developing immune tolerance of anaphylaxis-causing allergens in mice. The treatment resulted in significant effects with just one treatment in 90% of test cases.
The discovery involves generating a type of naturally occurring immune cell that sends a signal to reverse the hyper-immune response present in allergic reactions. That signal triggers another "off switch" that turns off reactive cells further along the allergic pathway.*Here's how the technique works:
•The key component of this research is dendritic cells, which serve as the gate-keepers of the immune system and are present in tissues in contact with the external environment, such as the skin and the inner lining of the nose, lungs, stomach and intestines.
•Gordon's pioneering treatment involves producing dendritic cells in a test tube and then exposing them to a unique mix of proteins, a vitamin A-related acid naturally occurring in the human gut, and to the allergen, in this case, peanut or ovalbumin (egg white protein). The modified dendritic cells are then reintroduced into the mouse.
•Using this technique, the researchers were able to nearly eliminate the allergic reaction by converting allergen-sensitive immune cells into cells that mimic the response seen in healthy, non-allergic individuals.
The treatment reduced the observed symptoms of anaphylaxis, and lowered other key protein markers in the allergic response by up to 90 per cent.
https://www.sciencedaily.com/releases/2016/10/161026133229.htm

Per the abstract, they "generated and characterized mature retinoic acid-skewed dendritic cells." (http://www.jacionline.org/article/S0091-6749(16)30969-1/abstract) I can't read the whole study, but I'm very curious about what exactly they did with the retinoic acid. A few months ago, I hypothesized that excess retinoic acid was connected to developing food allergies (http://petticoatgovernment.blogspot.com/2016/07/celiac-food-allergies-connected-to.html) and not in an inverse way; I thought that too much retinoic acid and its precursor retinal were interfering with RALDH2 activity, which appears crucial to immune tolerance. Perhaps I erred lumping retinal and retinoic acid together, or perhaps the timing of the exposure of the retinoic acid is crucial to developing the right kind of dendritic cell for reversing allergy. Or maybe while some retinoic acid is necessary to immune tolerance, an excess of retinoic acid causes the same problems as a deficiency, such as in this mouse study on excess Vitamin A, which found that it resulted in lower RALDH transcription subsequently - http://www.pnas.org/content/109/34/13668.full.pdf). I will have to wait until the study has been published (it's still an "article in press") to evaluate whether my hypothesis is either weakened or strengthened by the success of this new technique. Either way, I'm pleased to see such solid progress in this field!

Wednesday, October 26, 2016

Buckwheat

ScienceDaily just reported on a mouse study that found that the plant extract rutin helped diminish adiposity (i.e., lose weight):
To make their discovery, Jin and colleagues used both genetically obese mice and mice with diet-induced obesity as models. These mice were fed a regular diet, and supplemental rutin (1 mg/ml) was added to their drinking water. Rutin treatment significantly reduced adiposity, increased energy expenditure, and improved glucose homeostasis in both the genetically obese mice and the mice with diet-induced obesity. Specifically, the researchers found that rutin directly binds to and stabilizes SIRT1 (NAD-dependent deacetylase sirtuin-1), leading to hypoacetylation of PGC1α protein, which stimulates Tfam transactivation and eventually augments mitochondrial number and UCP1 activity in BAT. Rutin functions as a cold mimetic through activating a SIRT1-PGC1α-Tfam signaling cascade and increasing mitochondrial number and UCP1 activity in BAT. Rutin also induced brown-like (beige) adipocyte formation in subcutaneous adipose tissue in both obesity mouse models.
https://www.sciencedaily.com/releases/2016/10/161026105132.htm

Among other things, rutin is an aldose reductase inhibitor. (https://www.researchgate.net/publication/285826861_Inhibition_of_aldose_reductase_and_sorbitol_accumulation_by_dietary_rutin) Rutin is found in buckwheat, cranberries, citrus fruits, and many other edible plants (http://www.icpjonline.com/documents/Vol1Issue12/07.pdf). The rutin in buckwheat exhibits chelating and antioxidant activity, too. (https://www.ncbi.nlm.nih.gov/pubmed/27709826) I wonder how buckwheat tastes....

Tuesday, October 25, 2016

Sketchy invitations

I recently received an email inviting me to submit an article to a recently-started journal and even promising an honorarium if it published my article in the near future. I have a lot of ideas in the journal's field of exploratory pharmacology, so I sat down and started drafting a short commentary and hypothesis tonight. Then I noticed an English error in the invitation email.

Being a curious type, I started to look further into this new journal. The alleged publisher has three other journals, all started within the past year or two. They claim that one of the journals has already begun being indexed on Pubmed. So I checked Pubmed. No, they're not indexed. And very few journal articles have been published according to the websites of their four journals. This claimed publisher appears to be a scam, for what purpose I know not. Perhaps they were going to reject my article and then later agree to publish it for a fee. But if it's not a reputable and/or indexed journal, their throwing my article up on their little website doesn't get my article any wider audience than my blog could.

Beware of journal scams. On the bright side, though, thanks to this dubious email invitation, I forced myself to set some good ideas down into a coherent short article that I can submit elsewhere.

Monday, October 24, 2016

Fair skin and Parkinson's

It's been repeatedly observed that fair skin is linked to an increased risk of Parkinson's. Melanin is natural pigment that causes skin to be brown or black. Neuromelanin is a similar molecule that is found in the brain and, while still rather mysterious, appears to help prevent cell death in some parts of the brain. (https://en.wikipedia.org/wiki/Neuromelanin) Neuromelanin binds to (i.e., chelates) toxic metals, which helps protect the brain from them. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2582310/)

A study in 2015 found that the lighter someone's skin, the more likely they were to have brain structure abnormalities associated with Parkinson's:

 2015 Nov;30(13):1848-52. doi: 10.1002/mds.26427. Epub 2015 Sep 23.
Light pigmentation phenotype is correlated with increased substantia nigra echogenicity.
   OBJECTIVE:
This study was undertaken to address the question of whether pigmentation may be mechanistically linked withParkinson's disease.   METHODS:
In a cross-sectional, observational study, 116 healthy subjects received transcranial sonography of the substantia nigra. Pigmentation phenotype was assessed using the Fitzpatrick skin phototype classification, and five additional phenotypic pigmentation traits as well as a photographic method (Melanin index) in a subgroup of 46 subjects.   RESULTS:
Lighter skin phototype was associated with larger echogenic substantia nigra area and increased prevalence of abnormally enlarged echogenic substantia nigra area. The strongest association of substantia nigra echogenicity and phenotypic pigmentation traits was found for hair color and facial tanning.   INTERPRETATION:
Findings suggest an increasing prevalence of structural abnormality of substantia nigra with decreasing darkness of skin and thus may provide additional evidence in favor of a pathogenic link of pigmentation and Parkinson's disease.
https://www.ncbi.nlm.nih.gov/pubmed/26395561

Increased echogenicity of the substantia nigra is characteristically seen in Parkinson's disease. (http://jamanetwork.com/journals/jamaneurology/fullarticle/782224) Not only do I get painful sunburns and have to worry about skin cancer,* but I also have a heightened risk of developing Parkinson's disease.

*Melanoma risk and Parkinson's risk are related - https://www.ncbi.nlm.nih.gov/pubmed/26771684.

Friday, October 21, 2016

Aldose reductase inhibition

Aldose (or aldehyde) reductase is inhibited by several substances, including isoliquiritigenin (which I've been discussing in connection with licorice) and rutin (which interestingly is in tea - http://onlinelibrary.wiley.com/doi/10.1002/elan.200603496/abstract). Dietary sources of aldose reductase inhibition include spinach, cumin, fennel, lemon, basil, and black pepper. (https://www.ncbi.nlm.nih.gov/pubmed/19114390) Aldose reductase is most known for its role in glucose metabolism, but it has other functions including in norepinephrine metabolism (http://www.uniprot.org/uniprot/P15121).

Here are some studies indicating effects of inhibiting aldose reductase:


That last one is probably the most relevant to my quest to discover how to not get Parkinson's.

Thursday, October 20, 2016

Licorice

Licorice comes from two Greek terms meaning "sweet" and "root" and has been used for medicinal purposes for over 2000 years. (http://www.sciencedirect.com/science/article/pii/S0378874105002941)

The most well-known component of the licorice plant species is glycyrrhizin, which is very sweet and has some medical uses; however, excess consumption of glycyrrhizin can cause hypokalemia (low levels of potassium) and serious health problems. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498851/) One can buy licorice supplements which have had the glycyrrhizin removed. (https://en.wikipedia.org/wiki/Deglycyrrhizinated_licorice)

Another component of licorice is isoliquiritigenin which, besides being a sirtuin-activating compound (https://www.ncbi.nlm.nih.gov/pubmed/12939617, full text online at https://www.d.umn.edu/biology/documents/LiangPaper1.pdf) that could be good for fighting aging-related conditions (http://www.tandfonline.com/doi/abs/10.1517/13543770902762893?journalCode=ietp20) and being a sleeping aid (https://www.ncbi.nlm.nih.gov/pubmed/21945440), inhibits aldose reductase:
Traditionally in Japan, some kampo medicines (traditional oriental herbal prescriptions) have long been used for the treatment of diabetic neuropathy. We have found that some aldose reductase inhibitors are included among these drugs. We further investigated the components of glycyrrhizae radix, a constituent of some kampo medicines, and isolated six compounds (GUs 9-17). Among these, GU-17, identified as isoliquiritigenin, had the most potent aldose reductase inhibiting activity.
https://www.ncbi.nlm.nih.gov/pubmed/2118267

Tomorrow I'll go into how isoliquiritigenin's inhibition of aldose reductase might be helping the brain stave off Parkinson's. Apparently some scientists would argue with me that inhibition of aldose reductase does just the opposite:

Conference Paper: Aldose reductase-deficiency leads to more significant loss of dopaminergeric neurons with incresed levels of dopamine, tetrahydrobiopterin and free radical accumulation under experimental Parkinson's Disease condition

TitleAldose reductase-deficiency leads to more significant loss of dopaminergeric neurons with incresed levels of dopamine, tetrahydrobiopterin and free radical accumulation under experimental Parkinson's Disease condition
Authors
Issue Date2010
PublisherSociety for Neuroscience.
Citation
Neuroscience 2010 - 40th Annual Meeting, San Diego, CA., 13-17 November 2010. In Neuroscience 2010 - Final Program, 2010, Session 750, p. 20 Poster no. H15 How to Cite?
Descriptionhttp://www.sfn.org/am2010/pdf/final_program/final_program_b6.pdf
http://hub.hku.hk/handle/10722/161590

But they don't have a published paper that I can find, so I'm not sure what information or studies they base the title of their conference poster on. In general, searches on aldose reductase inhibition connect it with positive health outcomes. More tomorrow!

Wednesday, October 19, 2016

New topic - Parkinson's and smoking

I don't smoke. I never have and never will. Sometimes I find pleasing the smell of someone's else's cigarette wafting toward me from afar, but I have no desire to suck in all those poisons myself.

Smoking and smokeless tobacco are associated with lower Parkinson's risk, but not in those who have quit smoking. In fact, those who have quit smoking are more at risk of Parkinson's than those who have never smoked. (http://www.sciencedirect.com/science/article/pii/S1353802014004805) That suggests that 1) something in cigarettes could be accumulating in the body (I suspect cadmium), and 2) something in cigarettes partially protects against whatever (cadmium-induced?) brain insults are killing off dopaminergic neurons.

I might have come across two good candidates for the protective component of cigarettes. The first is nicotine, which in small doses--nicotine is in several commonly-eaten foods--appears to have some helpful aspects, which I'll blog about later. Unfortunately, nicotine patches appear ineffective in treating Parkinson's (https://www.ncbi.nlm.nih.gov/pubmed/14687854), so there's probably something else in cigarettes besides nicotine that is helping stave off Parkinson's. I suspect that second something is licorice. Isoliquiritigenin, a flavonoid in licorice (http://apps.who.int/medicinedocs/en/d/Js2200e/20.html), can apparently protect dopaminergic neurons from dying:

 2012;76(3):536-43.

Isoliquiritigenin isolated from licorice Glycyrrhiza uralensis prevents 6-hydroxydopamine-induced apoptosis in dopaminergic neurons.

Hwang CK, Chun HS.

Licorice (Glycyrrhiza uralensis) is a medicinal herb containing various bioactive components implicated in antioxidative, anti-inflammatory, antiviral, and neuroprotective effects, but the effects of licorice against Parkinson's disease (PD)-related dopaminergic cell death have not been studied. In this study, we investigated the protective effects of isoliquiritigenin (ISL) isolated from Glycyrrhiza uralensis on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in a dopaminergic cell line, SN4741. ISL (1 µM) significantly attenuated 6-OHDA (50 µM)-induced reactive oxygen species (ROS) and nitric oxide (NO) generation and apoptotic cell death. ISL pretreatment effectively suppressed 6-OHDA-mediated upregulation of Bax, p-c-Jun N-terminal kinase (JNK), p-p38 mitogen-activated protein (MAP) kinase, cytochrome c release, and caspase 3 activation. In addition, ISL significantly attenuated 6-OHDA-induced Bcl-2, brain-derived neurotrophic factor (BDNF), and mitochondrial membrane potential (MMP) reduction. Pharmacological inhibitors of the phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway reversed ISL-mediated neuroprotection against 6-OHDA toxicity in SN4741 cells. These results provide the first evidence that ISL can protect dopaminergic cells under oxidative stress conditions by regulating the apoptotic process.

https://www.ncbi.nlm.nih.gov/pubmed/22451397

Most of the world's licorice production is used in tobacco products. (http://www.npr.org/2012/09/07/160752629/the-secrets-in-a-cigarette) Some licorice makes it way into black licorice candy and root beer, but here in the USA, licorice is a very common ingredient in cigarettes and smokeless tobacco.

As a non-smoker, I'll be doing much more research on this, for I've lived in places with bad air pollution and I prefer to avoid developing Parkinson's.

Tuesday, October 18, 2016

Humming

Once in a while, I get sinusitis and sinus headaches. I've tried different home remedies to open up the ostia (openings) between my sinuses and my nose in order to promote sinus draining: steam, herbal teas, eating raw garlic (not fun), massage, and attempts to create vacuums in my upper respiratory passages (plugging my ears and nose and inhaling).

I recently came across something new to try. Humming helps exchange air between the nose and the sinuses.

Here we show that nasal NO [nitric oxide] levels increases dramatically during humming compared with normal quiet nasal exhalation. This effect is likely due to increased contribution of NO from the paranasal sinuses. Humming causes the air to oscillate, which in turn seems to increase the exchange of air between the sinuses and the nasal cavity. 
http://www.atsjournals.org/doi/full/10.1164/rccm.200202-138BC#.WAbKSlQrIdX

This exchange doesn't occur if the ostia are completely blocked, though. (https://www.ncbi.nlm.nih.gov/pubmed/15305890)

In 2006, a researcher in Sweden wrote a review on how humming affects ventilation between the sinuses and the nose. (https://openarchive.ki.se/xmlui/bitstream/handle/10616/38896/thesis.pdf?sequence=1) He mentions a case study where a man was able to clear out his sinuses by humming only: http://www.george-eby-research.com/html/chronic-rhinosinusitis.pdf. The case study was done by a man who used to sell zinc as a cure for colds, so I'm not sure how helpful it is, but it's interesting.

Humming has been tested and found to increase improvement of allergic rhinitis (hay fever) symptoms in patients who were given an intranasal steroid spray. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392338/) Unfortunately for my curiosity, the institute ethical committee didn't allow the researchers in that study to have a third group that only did humming without any steroid treatment, so it's unclear whether the benefit from humming was from increased delivery of the steroid spray to the sinuses or from the mere act of humming.

Next time I feel my sinuses start to become clogged, I'll try humming. Humming seems harmless, and I might as well do what I can to keep the sinuses open before they become blocked and cause sinus headaches.

Monday, October 17, 2016

Gastroparesis and migraines connection is H2S?

In the past couple of months, I've blogged about molybdenum helping with migraines as well as a sulfite-molybdenum theory of nausea and vomiting in pregnancy (NVP) that includes a claim that pregnancy-induced gastroparesis could be occurring as a result of endogenous hydrogen sulfide (H2S) production.

If elevated hydrogen sulfide is helping cause both gastroparesis and migraines, then there should some connection between the two. It turns out there is an association :

Gastroparesis is a chronic disorder manifested by delayed emptying of the stomach. Gastroparesis is a relatively common complication of diabetes. In a population of patients with symptoms of diabetic gastroparesis, the patients with cyclic symptom patterns had a higher incidence of migraine headaches (47 vs. 20%, p = 0.02) compared to patients without cyclic vomiting pattern (). Migraine attacks are associated with delayed gastric emptying (). This migraine-associated gastroparesis is a problem for the treatment of the migraine with oral medicines, like oral triptans (). Initially, delayed gastric emptying was found during migraine attacks, now there are also indications that in the interictal periods migraine patients have delayed gastric emptying. However, the studies done so far have been small and inconsistent in their results (), so further research in this topic is warranted.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240046/

Could an H2S-synthesis inhibitor help prevent gastroparesis? If so, I first nominate the lowly common vetch. Obviously not for use during pregnancy (http://petticoatgovernment.blogspot.com/2016/09/common-vetch-and-phocomelia.html), but we know vetch contains beta-cyanoalanine, which inhibits two H2S-synthesizing enzymes (https://www.ncbi.nlm.nih.gov/pubmed/23488457). A second possible suppressor of H2S biosynthesis is L-aminoethoxyvinylglycine (AVG) (https://www.ncbi.nlm.nih.gov/pubmed/23488457), which is widely used to delay ripening of plums, apples, pears, and other fruits (http://link.springer.com/article/10.1007/s10725-008-9312-5http://scialert.net/fulltext/?doi=ajcs.2014.320.333). AVG is even approved for use on organic fruit (http://www.sumitomo-chem.com.au/sites/default/files/literature/retain_progibb_cherry_technote_online_0.pdf). Gastroparesis patients are unlikely to get much AVG in their diet, seeing as fruit peels are warned against in many dietary guidelines for them; even if they did eat fruit peels with AVG sprayed on them, any resulting H2S-reduction might be trivial.

I'd love for someone to test whether common vetch or AVG can lessen gastroparesis symptoms. And perhaps migraines, too.

Friday, October 14, 2016

Wrapping up morning sickness posts for now

I'm a little bored with researching nausea and vomiting of pregnancy (NVP). Probably because I'm not pregnant myself and know only one person in the early months of pregnancy right now. I have an acquaintance who is 11 weeks pregnant and seeing some benefit from using molybdenum; her "morning sickness" is mostly stomach discomfort rather than nausea this time around (it's her fifth pregnancy, I believe), which fits my hypothesis that endogenous hydrogen sulfide production in the abdomen is part of a healthy pregnancy but will also tend to cause slower gastric emptying.

I've addressed why many home and medical remedies can ameliorate NVP in accordance with my theory of sulfite accumulation causing NVP. The main medical remedies I haven't addressed are antihistamines (very sedating, though) and dopamine antagonists (can cause heart rhythm abnormalities, movement disorders, etc.), both of which do far more to the body than just help it bear NVP (http://www.uptodate.com/contents/treatment-and-outcome-of-nausea-and-vomiting-of-pregnancy). I'll probably post more later as I stumble across connections between sulfite and these two kinds of medication. For example, there are hints that serotonin and dopamine increase production of hydrogen sulfide, the precursor of sulfite (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144905/, https://www.ncbi.nlm.nih.gov/pubmed/26593431).

I hope my theory is correct so that multi-effect medications such as antihistamines only rarely need to be used during pregnancy. Sleeping through early pregnancy is better than being conscious and miserable, but most pregnant women would prefer to not have their activities curtailed quite so sharply. A little curtailment is a good thing, to be sure. I think training for a marathon during the period of placental development is unwise at best. That placenta is growing into the uterus's endometrium, and it seems best to not have the uterus rattling up and down constantly during that process. But there's a big difference between sitting down and being asleep.

Thursday, October 13, 2016

Pineapple

I really like pineapple. Not enough to do this dance, but then not everyone has such smooth moves:



Thank you, husband, for showing this to me so I can stay up to date on viral videos.

Last summer, a relative experienced sinus congestion and pain after eating cheesy pizza. I had some bromelain--an enzyme extracted from pineapple stems--with me, and I'd read about it being helpful for various things. I think I had gotten most of my information about bromelain from this paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529416/. I gave my relative a pill or two of bromelain, and it made her sinus headache go away.

I think I've found a good argument in favor of pineapple pizza, which I enjoy even though many consider it an abomination. If the large quantity of cheese on a pizza can give one a sinus headache, then fresh pineapple with a little bromelain content is a logical addition to pizza.

A positive effect of bromelain on sinusitis symptoms has been found in clinical trials (https://www.ncbi.nlm.nih.gov/pubmed/17011407). Why does bromelain help with sinus pain? Is it inflammation reduction? (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870104/) Thinning of nasal mucus? (https://www.ncbi.nlm.nih.gov/pubmed/25712487) I don't know. I've experienced some relief when I have taken bromelain for sinus congestion and pain, but I don't like to take bromelain much because it seems to make my eyelashes droop into my eyes when I take it, which is annoying. Why would bromelain make my eyelashes turn toward my eyeballs anyway? I'm not comfortable with taking it regularly while all its effects remain unclear.

Plain pineapple, though, I'll happily eat in moderation. A 2014 article out of the Philippines reported that canned pineapple can lower the incidence of viral and bacterial infections in children (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258310/); this effect seems to have been from vitamins, not bromelain, as bromelain is an enzyme that is denatured by canning (http://serc.carleton.edu/sp/mnstep/activities/35683.html).

We need more research on bromelain to understand its effects on the body.

Wednesday, October 12, 2016

Why am I doing this nutrition research?

The first time I went outside the USA for more than a day trip was when I was 16 years old. My father took me out of school for a week (my grades didn't matter much because I was dropping out early to go to college the next fall anyway) so he could have a traveling companion on a trip to Cancun, Mexico. We went snorkeling, saw American college students get drunk, and visited Mayan ruins. But one of the things I found more intriguing than anything else was the local supermercado. Yes, I found the foreign grocery store to be an attraction. It had things I'd never seen before like fruit-flavored shelf-stable milk and bread with a giggle-worthy brand name ("Bimbo").

As years went by, I managed to get abroad a bit more. Germany, Poland, Austria, Philippines, South Korea, and then some countries in South America. And I continued to find the food stores one of the most interesting parts of my sojourns. I didn't care much about doing many typical touristy things, for beach outings left me sunburnt, but I loved seeing how the local people lived and learning about how they shopped for and ate food.

For the past three summers, our family has focused on learning about different countries: Russia, China, Germany, Lithuania, Zimbabwe, Bangladesh, Philippines, Japan, Peru, Mongolia, Canada, France, Italy, Senegal, Greece, Brazil, and Chile. For each country, I've read up about its cuisine so I could prepare meals for my family using typical foods from it. An unintended result for me was that I widened my knowledge of global eating patterns.

About a year ago, I took a free online course on vitamins from Wageningen University through EdX. My purpose in signing up for it was to learn information that would help me feed my family healthily. Not that I wasn't already feeding them fairly well, but I thought it would be good to know more about why fruits, vegetables, and whole grains were good for them.

Then about 10 months ago, I saw something talking about L-methylfolate being a better source of folate than folic acid. Due to a timing parallel between folic acid food fortification and the US's rise in autism, I'd been a little wary of folic acid supplementation for years. I still took folic acid during pregnancy, but my "regularly" wasn't the same as what my OB probably considered "regularly." 

So I looked into methylfolate and found myself falling down a rabbit hole of nutrition and medical research that I have yet to leave. And I don't want to leave it. The explosion of scientific knowledge in modern times and the unprecedented access that the internet gives us to even very recent findings has made this a great time to look at unsolved health problems from new angles, and my acquaintance with recipes and culinary preferences from other countries makes it easier for me to put together nutrition and epidemiology findings. I feel as though I'm doing math proofs, or at least connect-the-dot puzzles, with access to newly-discovered axioms and new data points. This is fun.

And that is why a stay-at-home homeschooling mother with degrees in law and math is posting what you find on this blog. No one pays me for it. Rather, someone would have to pay me to get me to stop.

Tuesday, October 11, 2016

Another molybdenum success story for migraine amelioration

Another friend who has suffered from migraines for years--she has to get weekly chiropractic adjustments to keep functioning due to her frequent migraines--tried molybdenum recently. She knew a bad migraine was coming on due to a weather shift (atmospheric pressure changes apparently trigger migraines in many who are prone to them), and took 250 mcg of a molybdenum supplement. Thirty minutes later her symptoms were noticeably reduced. After I told her that my first friend who tried molybdenum took a 500 mcg dose to make migraines go away, the second friend took an additional 250 mcg of molybdenum and experienced further benefit. She still had a headache--her migraines seem to be partly mechanical in origin, for they stem from something being damaged in her neck while doing pilates long ago--but it was bearable instead of the usual full-blown migraine.

She did experience one side effect: diarrhea, which is also something she experiences when she takes magnesium. The diarrhea is annoying enough that she is only going to take molybdenum when a migraine is coming on, but the molybdenum definitely helped her. If magnesium and molybdenum are supporting her body in turning sulfite into sulfate by facilitating suddenly higher levels of sulfite oxidase activity, diarrhea is exactly what one would expect to see, for there is anecdotal evidence that a sudden increase in sulfates in drinking water can trigger diarrhea and a 2012 study connected copper sulfate with diarrhea (https://www.ncbi.nlm.nih.gov/pubmed/22687538).

I've written to researchers in the field of migraines about sulfite possibly being a cause of migraine headaches, but the ones I contacted either ignored my emails or did not take seriously the possibility that sulfite could be involved. That is unfortunate, for there are many recently published research articles about how hydrogen sulfide, a precursor of sulfite, is made in the brain. I'll list a few here:

  • https://www.ncbi.nlm.nih.gov/pubmed/20149843: "In conclusion, H(2)S exerts a protective effect against cerebral hypoxia induced neuronal cell death via K(ATP)/PKC/ERK1/2/Hsp90 pathway. Our findings emphasize the important neuroprotective role of H(2)S in the brain during cerebral hypoxia."
  • https://www.ncbi.nlm.nih.gov/pubmed/12392053: Hydrogen sulfide as a neuromodulator.
  • https://www.ncbi.nlm.nih.gov/pubmed/25747482: "We as well as others have also shown that H2S has antioxidant, antiapoptotic, and anti-inflammatory properties against various neurodegenerative disorders such as stroke, Alzheimer's disease, and vascular dementia."
  • https://www.ncbi.nlm.nih.gov/pubmed/26019015: "During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent."
  • https://www.ncbi.nlm.nih.gov/pubmed/18754702: "Hydrogen sulfide (H2S) is recognized as a neuromodulator as well as neuroprotectant in the brain. H2S can be produced from cysteine by enzymes such as cystathionine beta-synthase. However, a mechanism for releasing H2S under physiologic conditions has not been identified. Here we show that H2S is released from bound sulfur, an intracellular store of sulfur, in neurons and astrocytes of mice and rats in the presence of physiologic concentrations of endogenous reducing substances glutathione and cysteine. The highest pH to release H2S from another sulfur store, acid-labile sulfur, which is localized mainly in mitochondria, is 5.4. Because mitochondria are not in the acidic condition, acid-labile sulfur may not be a physiologic source of H2S. Free H2S is immediately absorbed and stored as bound sulfur. Our novel method, using silver particles to measure free H2S, shows that free H2S is maintained at a low level in basal conditions. Alkalinization of the cytoplasm is required for effective release of H2S from bound sulfur, and this condition is achieved in astrocytes by the high concentrations of extracellular K+ that are normally present when nearby neurons are excited."
  • https://www.ncbi.nlm.nih.gov/pubmed/24800864: "Hydrogen sulfide (H2S) has been recognized as a signaling molecule as well as a cytoprotectant. It modulates neurotransmission, regulates vascular tone, and protects various tissues and organs, including neurons, the heart, and kidneys, from oxidative stress and ischemia-reperfusion injury."
  • https://www.ncbi.nlm.nih.gov/pubmed/24466346: "Hydrogen sulfide (H2S), a novel gaseous mediator, has been recognized as an important neuromodulator and neuroprotective agent in the central nervous system. The present study was undertaken to study the effects of exogenous H2S on traumatic brain injury (TBI) and the underlying mechanisms. The effects of exogenous H2S on TBI were examined by using measurement of brain edema, behavior assessment, propidium iodide (PI) staining, and Western blotting, respectively. Compared to TBI groups, H2S pretreatment had reduced brain edema, improved motor performance and ameliorated performance in Morris water maze test after TBI. Immunoblotting results showed that H2S pretreatment reversed TBI-induced cleavage of caspase-3 and decline of Bcl-2, suppressed LC3-II, Beclin-1 and Vps34 activation and maintained p62 level in injured cortex and hippocampus post TBI. The results suggest a protective effect and therapeutic potential of H2S in the treatment of brain injury and the protective effect against TBI may be associated with regulating apoptosis and autophagy."
  • https://www.ncbi.nlm.nih.gov/pubmed/26111628: "Endogenous production of H2S in the brain was significantly inhibited by SAH. The protein levels of the predominant H2S-generating enzymes in the brain, including cystathionineb-synthase (CBS) and 3-mercaptopyruvate sulfur transferase (3MST), were also correspondingly reduced by SAH, while treatment with NaHS restored H2S production and the expressions of CBS and 3MST. More importantly, NaHS treatment could significantly attenuate EBI (including brain edema, blood-brain barrier disruption, braincell apoptosis, inflammatory response, and cerebral vasospasm) after SAH. In vitro, H2S protects neurons and endothelial function by functioning as an antioxidant and antiapoptotic mediator. "
  • https://www.ncbi.nlm.nih.gov/pubmed/25388401: "The current study indicates that H2S may function as an effective neuromodulator to regulate striatal neurotransmission and provides insight into the potential of H2S for PD therapy."
  • https://www.ncbi.nlm.nih.gov/pubmed/24643521: "Hydrogen sulfide (H(2)S), a well-known toxic gas, is regarded as endogenous neuromodulator and plays multiple roles in the central nervous system under physiological and pathological states, especially in secondary neuronal injury. Recent studies have shown relatively high concentrations of hydrogen sulfide (H(2)S) in the brain and also cytoprotective effects of endogenous and exogenous H(2)S in models of in vitro and in vivo ischemic injury. H(2)S protects neurons by functioning as an anti-oxidant, anti-inflammatory, and anti-apoptotic mediator and by improving neurological function. Moreover, it protects neurons from glutamate toxicity."

Moreover, we know that when someone becomes deficient in molybdenum, headaches are one of the symptoms of that deficiency (http://ncp.sagepub.com/content/8/6/277.abstract). Also, we now know that sulfite oxidase deficiency affects the brain starting in the cerebral cortex and striatum (https://www.ncbi.nlm.nih.gov/pubmed/27523630). The cerebral cortex appears associated with migraine onset (https://www.ncbi.nlm.nih.gov/pubmed/24042483) and exhibits abnormalities in migraine patients (https://www.ncbi.nlm.nih.gov/pubmed/23533286).

If any readers of this blog know a physician, medical researcher, naturopath, nutritionist, or chiropractor who would be interested in looking into a sulfite connection to migraines, please tell them about this possibility. Testing molybdenum supplements for migraine alleviation is much less controversial than testing it (or any supplement) on patients with nausea and vomiting of pregnancy, for no one wants to take the tiniest chance of harming a developing fetus (which is as it should be).