Hello Progecitor, did you see that I sent you a personal message?
I am sorry for the late response, but I haven't had much spare time. Nevertheless I put the reply here so that others may also find some benefit.
Prospero was kind enough to bring to my attention that the PPAR-allopregnanolone axis could have a connection to Gilbert's syndrome.
Prospero:
"In Gilbert's your hormones are not knocked down, you have problems with glucuronidation, which breaks down 3adiol. So your 3adiol is not broken down, which inhibits 5a-reductase and causes low allopregnanolone, which leads with time to GabaA downregulation and AMPA receptor upregulation. Your high glutamate leads to activation of microglia. These problems with liver also stop methylation, which will be worsened because you are homozygous for COMT, and then you have bad conversion from noradrenaline into adrenaline. And obviously problems with histamine, serotonin, etc."I checked into it a bit, but the involvement of GABA seems controversial so far. You could be right, but I don't have any hormonal measurements and I haven't tried many GABAergic compounds either. I plan to have some hormonal tests done later this year and maybe some genetic tests next year, but the pandemic and my earnings don't make this easy. I highlighted some definitions as I am also just learning about these things and it makes this a bit easier to understand.
What I found so far:
3a-diol is a positive allosteric modulator of the GABA(A) receptor which means that it changes the receptor's response to stimulus.
Positive modulators increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e. affinity), increasing its ability to activate the receptor (i.e. efficacy), or both.[/i]
https://en.wikipedia.org/wiki/3%CE%B1-Androstanediolhttps://en.wikipedia.org/wiki/Allosteric_modulatorI checked the list on wiki and the comments I can make:
GABA(A) agonists: GABA, taurine, beta-alanine, allopregnanoloneGABA: I plan to buy to buy a supplement, but it hasn't been a priority so far.
Beta-alanine didn't do anything to POIS or my depression although I took it for two months last summer. Taurine increases the burning pain I feel which is a major indicator of my POIS. It can also cause a heartburn. However I haven't noticed any effect on depression or I was just not aware enough.
GABA(A) positive modulators: benzodiazepines, apigenin, niacinamide, 3a-diol, allopregnanoloneI took clonazepam (benzodiazepine) for years and it surely made me even more depressed and forgetful, however I don't think it really affected the other aspects of POIS or I just can't remember.
Apigenin and niacinamide are actually beneficial for my POIS.
Antagonists: I couldn't find any that is readily available to check.
Negative modulators: DHEA, amentoflavone, ciprofloxacinDHEA,: I haven't tried it yet but I want to in the future.
St. John's Wort (SJW) contains amentoflavone. I tried SJW twice, but I also took other POIS modulators at the time so I can't conclude anything yet.
Ciprofoxacin: I took some a few years ago, but I don't think it did anything to depression or I just don't remember.
https://en.wikipedia.org/wiki/GABAergicI actually bought an Apigenin product that also contains taurine. I only took it once, but I don't think it did much. This should theoretically up-regulate GABA(A) quite well. I am going to test it a bit more of course, but others could do as well.
Lemon balm (Melissa officinalis) is a GABA transaminase inhibitor.
Inhibition of GABA transaminase enzymes reduces the degradation of GABA, leading to increased neuronal GABA concentrations.https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acidIt is true that both apigenin and lemon balm help me, but they are also involved in FAAH inhibition.
The most potent and selective inhibitors of 5a-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoic acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea. Riboflavin was also identified as a 5a-reductase inhibitor.[/b]
https://en.wikipedia.org/wiki/5%CE%B1-ReductaseIt is a fairly reasonable suspicion that linolenic acid enhances my POIS. I have other problems with zinc that may be not directly related to POIS. I had some reaction to green tea, but I don't exactly remember what and I have to retest it before I can say any more. Riboflavin is also known as vitamin B2, but I haven't tested that separately, so I am not sure.
AMPA receptors play a key role in the generation and spread of epileptic seizures.https://en.wikipedia.org/wiki/AMPA_receptorIt is true that I took Rivotril (Clonazepam) for years, but I have never had any kind of seizures in my life, so it is unlikely that AMPA is up-regulated in my case. Clonazepam is also used to treat epilepsy if someone hasn't heard about benzos.
The substances resulting from glucuronidation are known as glucuronides (or glucuronosides) and are typically much more water-soluble than the non-glucuronic acid-containing substances from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or feces (via bile from the liver).Phenobarbital is an inducer of glucuronidation of both morphine and bilirubin.
Clonazepam is an inhibitor of morphine glucuronidation.
https://en.wikipedia.org/wiki/GlucuronidationA low dose of phenobarbital may be beneficial for me as I probably have problems with both morphine and bilirubin.
Phenobarbital is occasionally prescribed in low doses to aid in the conjugation of bilirubin in people with Crigler–Najjar syndrome, type II, or in patients with Gilbert's syndrome.https://en.wikipedia.org/wiki/PhenobarbitalIt is true that the only consistently bad blood parameter I have is an increased total bilirubin, however its value is only slightly increased. I also haven't experienced typical jaundice. There might had been some rare occasion when I had some slight yellowing of the conjunctiva, but usually it is only bloodshot and nothing else.
An elevated bilirubin level also seems to be a risk factor in COVID-19 infection, even though the infection wasn't very serious for me. Based on research bilirubin actually protects the virus against the antibodies.
https://advances.sciencemag.org/content/early/2021/04/22/sciadv.abg7607FAAH inhibition can affect GABA.A selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic intracellular membrane cisternae at perisomatic GABAergic symmetrical synapses.
Together, these findings are consistent with the possibility that constitutively active CB1 receptors substantially influence perisomatic GABA release probability and indicate that the synaptic effects of tonic 2-AG release are tightly controlled by presynaptic MGL activity and also by postsynaptic endovanilloid signaling and FAAH activity.
The findings indicate that constitutive CB1 activity has pivotal function in the tonic control of hippocampal GABA release. Moreover, the endocannabinoid 2-arachidonoylglycerol (2-AG) is continuously generated postsynaptically, but its synaptic effect is regulated strictly by presynaptic monoacylglycerol lipase activity. Finally, anandamide signaling antagonizes tonic 2-AG signaling via activation of postsynaptic transient receptor potential vanilloid TRPV1 receptors. This unexpected mechanistic diversity may be necessary to fine-tune GABA release probability under various physiological and pathophysiological conditions.https://www.jneurosci.org/content/35/27/10039.shortConstitutively active receptor: A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist.Niacinamide is a PPARA agonist just like PEA.Panthenol is known to improve epidermal differentiation and to be an effective anti?inflammatory agent. In these studies we demonstrated the effects of panthenol on reducing PGE2 levels and tissue damage induced by a strong inflammatory cocktail in an in vitro model. This is relevant to the clinical setting as PGE2 is known to be elevated in subjects with sensitive skin. PEA also proved effective at reducing the levels of PGE2 and IL?6 in vitro, both of which are UV?induced inflammatory biomarkers. In addition, PEA reduced the levels of thymic stromal lymphopoietin (TSLP), an inflammatory and pruritogenic biomarker, consistent with its reported itch?relief activity. PEA is also a putative PPARA agonist that may mitigate irritation via this mechanism also.
Niacinamide (NAM) was shown to enhance the expression of epidermal differentiation genes and increase cellular NAD. The former result is contradictory to that of Blander et al. and may reflect different testing methods, but the latter result is consistent with Rovito. Moreover, topical NADH, the reduced form of beta?nicotinamide adenine dinucleotide, is reported to be effective in the treatment of rosacea and contact dermatitis. Furthermore, the current work also demonstrated NAM?induced PPARA gene expression which is known to play an important role in regulating epidermal differentiation and reducing UV?induced erythema. Although speculative at this stage, it is likely that NAM may synergise with PEA in this mechanism.https://onlinelibrary.wiley.com/doi/full/10.1111/ics.12559PEA was first isolated from soy lecithin, egg yolk, and peanut meal.
One way in which PEA can indirectly activate CB1 and CB2 receptors is by inhibiting the expression of fatty acid amide hydrolase (FAAH), an enzyme that degrades the CB1 agonist AEA. The transient receptor potential vanilloid receptor type 1 (TRPV1) channels, which are also endocannabinoid targets, can also be indirectly activated by PEA. From these activities, it can be surmised that PEA needs synergistic actions among several mechanisms for it to be able to produce its effects.https://blog.metagenics.com/post/2019/10/17/get-to-know-pea-and-its-history/I took a soy lecithin supplement a few years ago and I think it helped a little at the time, so I will need to test it again.
Intracellular NAD+ (nicotinamide adenine dinucleotide) concentrations reflect a balance between biosynthesis from discrete dietary precursors and "consumption" by enzymes that cleave NAD+ to release nicotinamide. Stressors such as ischemia have been known to induce NAD+ consuming enzymes such as poly-ADP-ribose polymerases and CD38; induction of these enzymes lowers NAD+. Tran and colleagues recently reported that renal tubular cell NAD+ levels are suppressed in models of acute kidney injury (AKI) and that this reduction of NAD+ may blunt fatty acid oxidation, reduce adenosine triphosphate generation, and elevate susceptibility to AKI stressors. Unexpectedly, they found that the stress-related fall in NAD+ was not only a consequence of increased consumption but also the result of decreased biosynthesis. In seeking a mechanism of decreased NAD+ biosynthesis, this study identified a novel function of the mitochondrial biogenesis regulator PPAR-gamma-coactivator-1alpha (PGC1a) to coordinately induce the enzymes that sequentially convert the amino acid tryptophan to NAD+. This series of enzymes is collectively referred to as the "de novo" or "kynurenine" (one of the intermediates between tryptophan and NAD+) biosynthesis pathway for NAD+. This study showed that renal tubular PGC1a expression defends the nephron against unrelated stressors, and that artificial augmentation of NAD+ could effectively mimic PGC1a's salutary effects in the tubule. Hence, a common PGC1a-NAD+ "axis" was described for kidney protection across rodent models of ischemia, inflammation, and nephrotoxicity.
The authors then embarked on a clinical trial to augment NAD+ among high-risk patients. Since the de novo pathway appeared to be blocked by QPRT suppression, they chose to administer nicotinamide (also referred to as niacinamide), the base version of vitamin B3, which the team had shown to boost renal NAD+ through another biosynthetic route known as the "salvage" pathway.https://sci-hub.se/https://www.karger.com/Article/Abstract/500168This article greatly proves what Prospero said, although I still need to confirm it in my case.
Specifically, we focus on the function of the peroxisome proliferator–activated receptor (PPARA), a target for PEA, which is best known for its role in reducing inflammation by decreasing cytokines, pro-inflammatory enzymes and oxidative stress. For this, PPARA agonists act as neuroprotectants in various neurological disorders like Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral ischemia. However, recent literature in the field suggest that PPARA has emerged as a new target that is useful as a novel approach to treat mood disorders by engaging neurosteroid biosynthesis.
PPARA activation has been shown as a natural response to stress, having the ability to mediate and modulate the stress response. In healthy adults, PEA, an endogenous PPARA agonist, significantly increase after clinical stress tests, corresponding with increased cortisol levels. PEA levels increase when healthy individuals experience pain or a depressed mood transiently. However, the levels of PEA in PTSD are low, suggesting a significant role in emotion regulation. As such, endogenous and synthetic PPARA ligands have predictably and successfully stabilized emotions in preclinical models.
Given that allopregnanolone directly binds this receptor, a reduction of allopregnanolone levels correlate to reduced GABA(A) receptor activity and dysfunctional behavior.
Intriguingly, the allopregnanolone level in the blood and CSF are reduced in patients of major depressive disorder (MDD), impulsive aggression, premenstrual dysphoric disorder, PTSD and other disorders of mood and emotions.
As a specific example, the allopregnanolone level in the CSF of female PTSD patients were 40% lower than in controls, and the allopregnanolone/dehydroepiandrosterone (DHEA) ratio negatively correlates with PTSD re-experiencing. To this end, studies are being pursued to verify lower levels of allopregnanolone during pregnancy as a predictor of postpartum depression (PPD).
Early studies have shown that allopregnanolone levels in the brain increase to levels that can activate the GABA receptors, during acute stressful events. Subsequently, it has been further hypothesized that the enhancement of GABAergic transmission decreases HPA activity and contributes to the behavioral stress response. Protracted stress, on the other hand, downregulates allopregnanolone biosynthesis. The decrease of allopregnanolone was the result of reduced levels of 5a-reductase type I mRNA and protein following social isolation. Hence, these findings suggest that allopregnanolone, its precursors, and analogs of allopregnanolone are suitable treatments for emotional regulation. For example, exogenous allopregnanolone attenuated the contextual fear response in a dose-dependent manner. In a similar murine social isolation model of PTSD, researchers showed that allopregnanolone treatment normalized HPA responsiveness and interrupted depressive- and anxiety-like behavior, which are hallmarks of clinical PTSD.
The summaries above suggest that the role of allopregnanolone in the progression and recovery of psychiatric disorders is similar to the emerging role of PPARA. Importantly, these similarities are not limited to their function in emotion regulation. Comparable actions of PPARA and allopregnanolone have also been observed across cognition, neurogenesis, neuroinflammation, neurodegeneration, and substance use disorder. Raso et al. suggest that the PPARA and allopregnanolone are different substrates of the same mechanism, whereby PEA-induced activation of PPARA regulates the biogenesis of allopregnanolone in astrocytes. To this end, when astrocytes were treated with PEA in vitro, an increased expression of enzymes that are crucial to allopregnanolone biosynthesis [steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc)] were reported along with increased cytoplasmic concentrations of allopregnanolone. This interdependent relationship between PPARA and allopregnanolone has also been alluded to in studies of pain perception. In studies of acute and persistent pain, researchers showed that the usual anti-nociceptive activity of PEA was reduced when activity of enzyme 5a-reductase and P450scc were blocked. PEA restored enzyme expression and increased allopregnanolone level in the spinal cord. Further support for this relationship was shown when PEA was used as neuroprotector and regulator of the pentobarbital-evoked hypnotic effect. In this case, PEA increased the expression of relevant enzymes and allopregnanolone concentrations in the spinal cord.
These findings suggest that allopregnanolone functions downstream of PPARA to mediate its therapeutic effects, thus, we further hypothesize that part of the mechanism of action of PPARA includes an upregulation of the biosynthesis of neurosteroids, by upregulating the expression of crucial neurosteroidogenic enzymes. A recent study by Locci and Pinna further demonstrated the allopregnanolone-dependent effect of PPARA-activation. In this study, a single dose of a PPARA agonist, PEA or GW7647, normalized the levels of allopregnanolone in socially isolated mice, improved depressive-like and anxiolytic-like behavior, and facilitated impaired extinction of fear memory. The therapeutic-like effects of the PPARA agonists were however obstructed by genetic ablation of PPARA, antagonism of PPARA, and inhibition of neurosteroidogenic enzymes. This and previous studies further support a possible PPARA-allopregnanolone biomarker axis in PTSD, and a new therapeutic target for emotional disorders.
Given the new relationship pointed out in this opinion article, the biochemical profile of PTSD may include a PPAR–allopregnanolone biochemical axis such that subpopulations of PTSD patients may display reduced allopregnanolone levels that can be increased by PPARA activation, only in allopregnanolone-deficient patients. Other components of the profile can also include changes in GABA(A) receptor subunit expression, decreased levels of endogenous fatty acid amides such as PEA and OEA, or downregulated expression of PPARA.https://www.frontiersin.org/articles/10.3389/fphar.2018.00998/fullAnother great article about the PPAR-neurosteroid axis that also lists great PPAR modulator nutrients.
In the pathogenesis of mood disorders, including major depressive disorder (MDD) and postpartum depression (PPD), both neuroinflammation and glutamate-mediated excitotoxicity mechanisms (neuronal death through glutamate-based over-activated stimulation) have been suggested to play a key role.
Interestingly, allopregnanolone reduces calcium influx through the activation of GABA(A) receptors expressed on cerebrocortical nerve terminals leading to decreased glutamate release and glial activation, supporting neuroprotective effects.
Locally produced allopregnanolone is responsible for the fine-tuning of GABA(A) receptors in corticolimbic glutamatergic neurons, a mechanism that has been linked with improvement of behavioral dysfunction. At this level, allopregnanolone may conceivably dampen neuroinflammatory processes following activation of glial-type GABA(A) receptors. Recent evidence shows allopregnanolone, following activation of a2-containing GABA(A) receptors and subsequent inhibition of toll-like receptor 4, can regulate the immune response by inhibiting proinflammatory processes.
Endogenously produced allopregnanolone plays a neurophysiological role in the fine-tuning of the GABA(A) receptors to GABAmimetics, positive allosteric modulators, and GABA agonists.
By this mechanism, allopregnanolone also regulates emotional behavior and stress-responses.
Moreover, decreased allopregnanolone levels in the postpartum period is associated with increased inflammation likely by activated microglia, which releases pro-inflammatory biomarkers, such as IL-1, IL-6 and TNF-a via the NFkB pathway that is also regulated by PPAR. Another mechanism involves the toll-like receptor 4 (TLR4), which, once activated by different triggers such as lipopolysaccharide (LPS), pathogen-associated molecular patterns (PAMPs), alcohol, stress or decreased levels of pregnenolone, forms a complex with intracellular co-activators, such as TIR Domain-Containing Adaptor Protein (TIRAP) and TRIF-related Adaptor Molecule (TRAM) to initiate a pro-inflammatory cascade that leads to NFkB activation and pro-inflammatory cytokines release. Low levels of allopregnanolone lead to increased calcium channel activity in activated nerve terminals and increased release of glutamate that facilitates excitotoxicity mechanisms. Unhealthy diets, including high fatty diets or alcohol abuse play deleterious effects on PPAR function that fails to regulate pro-inflammatory processes and greatly contribute to the neuroinflammation mechanisms underlying the pathogenesis of major depression and, possibly, PPD.
At the same time, increased allopregnanolone levels in neurons may stimulate brain derived neurotropic factor (BDNF) and exert important neuroprotective functions. We suggest that healthy diets enriched in micronutrients that are PPAR-agonists by enhancing the PPAR-allopregnanolone axis and decreasing inflammation may offer an alternative strategy to pharmacological treatments to prevent and safely treat mood disorders, including PPD.
Brexanolone, despite its proven high efficacy, showed adverse effects such as headache, dizziness, somnolence, and, in some cases, excessive sedation, which may complicate the safety of its use.
Together with PPARG, PPARA is deeply involved in several physiological and pathological conditions, including regulation of mitochondrial and proteasomal function, neuroinflammation, oxidative stress and neurodegeneration, which are considered key pathogenetic mechanisms involved in stress-related disorders, including anxiety and depression.
Intriguingly, PPAR mediates anti-inflammatory responses under several pathophysiological conditions and can stimulate biosynthesis of neurosteroids, such as allopregnanolone, with documented anti-inflammatory actions and role in improving mood symptoms, which suggests that the PPAR-neurosteroid axis may have a pivotal function in the modulation of mood by regulating inflammatory processes.
Intriguingly, PPARA activation stimulates the biosynthesis of allopregnanolone that in addition to elevating mood, has also been associated with an anti-inflammatory effect. Indeed, allopregnanolone binds at GABA(A) receptors expressed both on microglia and astrocytes and in glutamatergic pyramidal neurons, and it mediates anti-inflmmatory effects through blocking toll-like receptor 4. This results in NFkB inhibition. Allopregnanolone's binding at GABA(A) receptors on monocytoid cells leads to diminished production of inflammatory mediators by these cells. Further, GABA suppresses astrocytes and microglia inflammatory responses to lipopolysaccharide (LPS) and INF-g by inhibiting the NFkB activation pathway and P38 MAP kinase. This process leads to a decreased release of pro-inflammatory cytokines, such as TNF-a and IL-6 and results in an attenuation of neurotoxicity in vitro. Interesting, similar anti-inflammatory effects were observed following the administration of the GABA(A) receptor agonist, muscimol and the GABA(B) receptor agonist, baclofen, suggesting the direct role of both types of GABA receptors in reducing neuroinflammation. Interestingly, GABA(A) receptors are also expressed in macrophages and lymphocytes T cells and their activation produces anti-inflammatory effects. In addition, neuroinflammation-associated release of glutamate from activated microglia has been implicated in the progression of neurodegenerative diseases, including Alzheimer's and Parkinson's disease and recent studies have shown that PPARs can modulate neurotoxicity by inhibiting glutamate release in LPS-activated microglia.
In vitro and in vivo studies show that 17B-estradiol, progesterone, and allopregnanolone reduce microglial-mediated inflammation.
A combined therapy of pioglitazone with the SSRI antidepressant, citalopram, showed a higher pharmacological response and remission rate, and rapid onset compared to citalopram alone. In another study, a 12-week pioglitazone administration induced antidepressant effects in patients with comorbid insulin resistance, supporting a link between depression and metabolic dysregulation.
Green tea, broccoli, onions, and berries are enriched in phytonutrients, such as carotenoids, ellagic acid, flavonoids, resveratrol, glucosinolates, and phytoestrogens that help fighting oxidation and inflammation. Naringenin, quercetin, hydrocaffeic acid, procyanidins, and anthocyanidins belong to the class of flavonoids and exert anti-inflammatory effects in vivo and in vitro by inhibiting the expression of iNOS, ICAM-1, MCP-1, COX-2, TNF-a, IL-1B and IL-6 expression.
PEA is abundant in egg yolk, soy oil, peanut oil, and corn, peas and beans, tomatoes and potatoes.
In addition, zinc modulates PPARG signaling, which is impaired in zinc deficiency.
In rodents, for instance, high-fat diets alter PPAR pathway causing abnormalities in the microbiome that can be reversed by rosiglitazone, a PPARG agonist. Several natural bioactive compounds act on PPARs, including the tea plant, soybeans, palm oil, ginger, grapes and wine as well as a number of culinary herbs and spices (e.g. Origanum vulgare, Rosmarinus officinalis, Salvia officinalis, Thymus vulgaris).
Curcumin has also shown anti-inflammatory and antioxidant effects by increasing PPARG activity. OEA, which is a natural metabolite of oleic acid, and an endogenous PPARA modulator, shows anti-inflammatory activity. Then, foods rich in oleic acid, such as olive oil, avocado and almond oil can be used as part of the anti-inflammatory dietary patterns.
In addition, omega-3 (or n-3) PUFAs and their metabolites are natural ligands for PPARG.
EPA and DHA supplementation have been shown to decrease levels of key inflammatory cytokines TNF-a, IL-1B, IL-6, and IL-8.
Dietary flavonoids found in fruits and vegetables exert anti-inflammatory effects, as well by suppressing microglia activation through the PPARG mediated pathway.
Resveratrol, which is present at high levels in red grapes, nuts, and pomegranates, exerts metabolic, antioxidant, and anti-inflammatory activities, as well as neuroprotective effects through PPAR-activation. Similarly, quercetin induced antidepressant-like effect in the unpredictable chronic mild stress animal model of depression and induces antioxidant, anti-inflammatory activities, reduces excitotoxicity and augments 5-HT levels, linking the role of inflammation to depression. Foods rich in quercetin are capers, goji berries, onions, asparagus, spinach and red grapes. Resveratrol and quercetin are polyphenolic compounds that improve metabolic syndrome by altering PPAR expression. PEA shows antidepressant effects by binding at its main target, PPARA, and may increase endogenous levels of the endocannabinoids, anandamide (AEA) and 2-arachinoylglycerol (2-AG) and exert anti-inflammatory, analgesic, and neuroprotective properties.
We propose that PPAR might work in synergism with stimulation of neurosteroid biosynthesis to exert their beneficial effects by decreasing inflammation and relieving mood symptoms. Intriguingly, PEA-induced PPARA activation engages allopregnanolone levels in frontal cortex, hippocampus and amygdala to improve behavioral abnormalities in an animal model of stress-induced mood disorders
Moreover, allopregnanolone is also involved in BDNF expression and neurogenesis. In socially isolated mice reduced levels of allopregnanolone in corticolimbic areas are associated with BDNF deficiency, reduced neurogenesis and depressive- and anxiety-like behavior, supporting a multifunctional role of allopregnanolone for depression and anxiety prevention.
Intriguingly, studies have suggested that PPARA activation by administering synthetic PPARA agonists, including fenofibrate, is associated with stimulation of BDNF signaling cascade and improvement of behavioral dysfunction.
Moreover, FDA-approved synthetic PPARA agonists, including the fibrates (e.g., fenofibrate, clofibrate), prescribed for the treatment of hypercholesterolemia, could be repurposed to treat mood disorders by targeting the PPAR-allopregnanolone axis.Table 1. contains a list of Functional Foods rich in micronutrients that activate PPARA and PPARG and induce pharmacological effects!
https://www.sciencedirect.com/science/article/pii/S2352289520300126I think PPARA agonists may help me, so I will have to thoroughly test them.
A short list of PPARA agonists: PEA (soy lecithin, egg yolk, and peanut meal) niacinamide, oleic acid (olive oil, avocado and almond oil), fibrates (fenofibrate, clofibrate).
