The case for endogenous and exogenous sigma one receptor inhibitors, specifically the neurosteroid, progesterone, and the sigma one receptor antagonist, Haloperidol, as the cause of mitochondrial dysfunction leading to Alzheimer’s and Parkinson’s diseases.
Submitted: Biostockclub 12/19/18
1. Not all central nervous system diseases are due to this cause. This is limited to evidence gathered implicating the above agents in Alzheimer’s disease and Parkinson’s disease. Other central nervous system diseases may be symptomatically improved by sigma one receptor agonists while the cause remains inconclusively linked to the neurosteroid, progesterone and the sigma one receptor antagonist Haloperidol. Some of these diseases are genetic in origin.
2. A paper published by Tangui Maurice in 1999 states that two most potent inhibitors of the sigma one receptor are the neurosteroid progesterone and the antipsychotic drug Haloperdiol. (1)
3. Evidence supporting the case for progesterone inhibiting the sigma one receptor and resulting in Alzheimer’s disease later in life include the timing of widespread exogenous use. Birth control pills were approved as a contraception method in the United States in the year 1960. (2) Norethindrone, a synthetic version of the natural hormone progesterone was contained in the first birth control pills. It is important to note that the birth control pills that were being utilized in 1970 contained mostly progesterone with much lower ratio of estrogen. (3) The progesterone was taken to block ovulation. And the pill contained 10 times the amount of the hormone needed to block ovulation. “The first brand, Enovid, had a lot more hormones in it than needed to prevent pregnancy. It contained 10,000 micrograms of progestin and 150 micrograms of estrogen. In comparison, today’s lower-dose pills are more likely to contain 50–150 micrograms of progestin and 20–50 micrograms of estrogen.” (Knowles & Ringle, 1998; Tone, 2001).” (4) Women using the pill as a form of birth control between 1960 and 1970 who were 20 or 30 years old at the time are now 70 or 80 years old. Alzheimer’s disease occurs twice as often and women as in men.
4. Since the progesterone is the most potent inhibitor of the sigma one receptor ( also GABA and NMDA), the sigma one receptor is unable to perform the function of regulating normal neuronal health for several days each month. (PMS occurs during the high progesterone level phase and PMS symptoms include cognitive impairment, agitation, mood swings, which mimic mild AD temporarily.
5. Fast forward 50 years and the mitochondrial dysfunction has had years to degenerate without repair ( no sigma one receptor agonist restoring the cellular health) and misfolded proteins have given way to a slow systematic buildup of amyloid plaque and tau tangles which along with cognitive impairment - memory loss, changes in mood, agitation, and restlessness, manifest as Alzheimer’s disease years later.
6. High progesterone levels are not only correlated with birth control pills as some women have high endogenous progesterone levels all of their childbearing life until menopause.
7. Pregnancies also increase progesterone levels throughout pregnancy and an increased number of pregnancies is correlated with greater risk of Alzheimer’s disease later in life. Women who have 5 pregnancies or more are at greater risk for AD later in life. (5) Additionally, pregnancy reduces the sigma one receptor function in the brain. (5 also)
8. Top 10 countries where the pill was approved by year versus prevalence of Alzheimer’s disease later in life 10 countries with highest incidence of AD today along with the year the contraceptive birth control pill was approved for use in that country: Finland 1962 US 1960 Canada 1969 Iceland 1962-state subsidized Sweden 1962 Switzerland 1962 Norway 1963 Denmark 1962 * Netherlands 1962 Belgium 1962 (6) (7) * linked to higher suicide and depression rate (8)
Please note that in these countries, the preferred method of contraception “At The Time” was the oral pill. This is not the case for these countries today. (9) - on this cite, please note map of Australia, which is dementia ridden (emphasis).
9. Countries with low incidence of Alzheimer’s disease - these all rank as extremely low incidence today, despite many now having become modernized, industrial countries with better standard of living (meaning, they all have McDonalds, Starbucks, education, and skyscrapers) Countries where the pill was not widely used in the 60’s and 70’s and/or other birth control methods were used: India Still haven’t approved pill Cambodia < 20% use any Georgia < 20% use any Singapore none during 60’s/70s Bangladesh < 8% usage Thailand Mostly poorer, less educated countries in Southeast Asia, South/Central America in the 60’s and 70’s. with no use of oral contraception at that time. (10)
10. These correlations have nothing to do with the standard of living or healthcare systems or socioeconomic conditions in each country during the 60’s and 70’s...elderly people in those countries had different lifestyles but still exist with lower incidence of AD. In fact, the more industrialized higher standard of living countries where women wanted more sexual freedom without consequences now have the greatest incidence of Alzheimer’s disease. This could have to do with the diet and exercise and lifestyles however diet and lifestyle vary across the globe and this control remains the same.
11. Note lowest incidence of Alzheimer’s disease and cuisine containing the potent progesterone inhibitor turmeric. India, Cambodia, and several Southeast Asian countries have the lowest Alzheimer’s disease prevalence and cuisine which consists of the highest level of turmeric and is used in its fresh form. Turmeric is a potent progesterone inhibitor. (11)
12. Hormone replacement therapy after menopause contains progesterone and is also a contributing factor to this cause. (12) “In 1986, one of the earliest HRT trials found that women with dementia taking estradiol showed significant improvements in attention, orientation, mood, and social interaction [4]. But this study only included seven patients and no control group.”
Same source on use of both hormones, estrogen and progesterone: “Based on these and other promising findings, the Women's Health Initiative Memory Study (WHIMS) launched in 1991. It included over 4,500 postmenopausal women and examined the effects of estrogen plus progestin HRT on the incidence of dementia and mild cognitive impairment [5]. It found that HRT did not improve cognitive function, and it increased dementia risk for postmenopausal women over the age of 65.”
13. The pill was approved in the United States in 1960. The sigma one receptor was discovered in 1984. It’s function was not known but was theorized through the 1990s. Two papers, in 1998 and 1999, propose sigma one receptor role is maintaining neurological health. T. Maurice paper is one. However by 1999, Alzheimer’s disease was already being treated by medical science as the product of amyloid plaque and the focus was on clearing it. Nothing had failed yet and this was still a new notion. Five drugs were approved for Alzheimer’s yet none of these was an amyloid plaque clearing drug nor a sigma one receptor agonist. Despite this fact, no more detective work was being done to look for another cause.
14. When the pill turned 50 in 2010 it was becoming obvious that an epidemic was present but so much time had passed and the Amyloid theory was cemented and was being taught exclusively at that time. No one went back to look for clues at the scene of the crime– the original date when this began– it was impossible to know when it began because symptoms are silent and slow for this disease.
15. Once Anavex achieved limited success with the sigma one receptor agonist A2– 73, I looked at the trend line and prevalence and where and who were affected and read about Sigma one receptors. I was most curious about what blocks them and keeps them from working given their natural function of maintaining central nervous system function. I learned that the most potent culprit is progesterone. I then traced the present day victims back to a time when they could have possibly been exposed to higher levels of progesterone. It was then that I learned that the pill containing higher levels was approved when they were all in their early childbearing years.
16. However I needed to search for further evidence. Men also suffer from high endogenous progesterone levels occasionally. They also suffer a higher rate of head trauma’s which could lead to damage to the brain neurons along with subsequent mitochondrial dysfunction and damage to sigma one receptors (this was mostly due to military service, professional and amateur sports prior to protective head gear, and higher work place risk of trauma.)
17. One possibility I entertained is that progesterone could cause amyloid buildup, directly, without knocking out the sigma one receptor. However, the Sigma one receptor, if functioning properly, would mitigate damage to the neurons in the brain caused by progesterone, as that is its primary role.
18. In order to test the hypothesis that the sigma one receptor has to be knocked out by inhibitors in order to be proven to play a vital role in protecting the brain from Alzheimer’s disease in later life, I looked at the second most potent Sigma one receptor inhibitor, the antipsychotic drug, Haloperidol. This inhibitor, too, was in widespread use in treating soldiers returning from Vietnam in the early 1970s. Mostly used as a pharmaceutical restraint agent. This was and still is (in the VA) the standard treatment of post traumatic stress disorder, psychotic episodes of flashback, exposure to agents which were toxic and caused psychosis, and other mental illnesses. The men treated with this drug which inhibits the Sigma one receptor went on to exhibit and manifest Parkinson’s disease at red flag rates compared to those not treated with the drug. This drug is contraindicated in patients with Parkinson’s disease and side effects include impaired motor skills. “Common (>1% incidence) * Extrapyramidal side effects including: * Akathisia (motor restlessness) * Dystonia (continuous spasms and muscle contractions) * Muscle rigidity * Parkinsonism (characteristic symptoms such as rigidity)” Additionally, when this drug was given to patients with mild cognitive impairment or Alzheimer’s disease, it worsened their condition. “A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to people with Alzheimer's with mild behavioural problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.[37]” (13) Additionally, Vietnam Veterans commit suicide at the rate of 22/day. (Sigma one block connection?)
19. What are the chances that the two strongest inhibitors of the sigma one receptor when taken over years would lead to full-blown Alzheimer’s and Parkinson’s at a disproportionate rate without regard to other cultural differences if the sigma one receptor were not the governing link which had been interfered with?
20. T. Maurice’s paper, 1999, also states the purported role the sigma one receptor plays in regulating proper brain function in the areas of: sleep, agitation, mood, seizures, and memory impairment - exactly the resume of what A2-73 pre-clinical trials demonstrated. (14)
21. Additionally, this theory explains the extraordinary response to A2-73, sigma one receptor agonist, among the APOE4 genetic Alzheimer’s patients because their disease state originates from a gene proclivity and not progesterone.
I purport that the epidemic we face today of misfolded proteins originated mainly from progesterone and Haloperidol inhibiting the sigma one receptor. If one excludes these extraordinary factors, we would be left with cases owing strictly to age and neurodegeneration along with brain injuries and infectious diseases which would make Alzheimer’s disease present today but not pervasive. Amyloid and tau are symptoms not the cause and if one were to administer progesterone to a patient along with an A2-73 the drug would fail to agonize the receptor, due to inhibitory properties of the hormone.
The genomic work done by Anavex is not the key to finding the cause of CNS diseases, it is to determine which patients should respond best to the agonist. This is speculation about the drug working but the central theme of this case is for the initial cause of the diseases. In the absence of a blocked Sigma one receptor, A2-73 if taken without an inhibitor concomitantly, has the potential to maintain neuronal health as described by T. Maurice in several papers outlining the s1r agonist’s ability to effectively prevent and treat several central nervous system maladies.
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