Nerve growth factor (NGF) stimulation

[Progecitor]

Based on recent experiences I can confirm that nerve growth factor (NGF) as a neurotrophin likely plays a critical role in my POIS case. I bought a new hericium and black maca extract product and both seemed to produce a noticeable benefit individually, but when I combined them along with saffron and a number of usual stuff I simply felt so well. Having an O still produced the emergence of some symptoms, but every aspect of POIS was clearly significantly reduced. Specifically the depression felt quite reduced, the eye only became a little bloodshot and the burning pain was very significantly reduced though not completely. I have already tried numerous mushrooms, but for some reason lion's mane (Hericium) is particularly splendid in its effectiveness. This made me wonder what the reason could be. As NGF stimulation is rather indicated as part of lion's mane mushroom's action I was trying to see how it could fit into the POIS picture. As it turns out it can very much do so. NGF clearly has a significant role in reproductive function, which is a crucial fact from our point of view.
As NGF production seems to be at least partly under the control of ERbeta expression, it could easily explain the neuroprotective function of ERbeta. Conversely it could also explain why I experienced an anti-depressive effect with several ERbeta agonists. Furthermore considering that most supposed testosterone boosting supplements also activate ERbeta a logical assumption would be that this happens through the ERbeta-NGF-testosterone axis. All this also means that lion's mane may be considered a potentially superior testosterone booster.
Care should be taken with such a stack though, as NGF is responsible for mast cell accumulation as well. Even so my case seems to be associated more to neurodegenerative diseases like Alzheimer’s disease, which is plenty scary nonetheless.

First some evidence that such a combination (lion's mane+maca+saffron) could actually increase NGF:

- Lion's mane mushroom (Hericium erinaceus)
The presence of erinacines resulted in greater amounts of NGF secreted than for hericenones. As a result, erinacines have been studied and found to be of value as potential alternatives for treating Alzheimer’s disease and peripheral nerve regeneration.
https://scholar.ufs.ac.za/server/api/core/bitstreams/deaf3b8c-d05b-427e-85ed-7a32d7fedcfb/content

- Diosgenin (black maca extract):
Neuroprotective role of Diosgenin, a NGF stimulator, against Abeta (1–42) induced neurotoxicity in animal model of Alzheimer’s disease
https://link.springer.com/article/10.1007/s11011-021-00880-8

- Saffron
Continued training + crocin significantly increased NGF and continued training + crocin increased NGF more than continued training, crocin, interval training, and interval training + crocin group.
http://feyz.kaums.ac.ir/article-1-3763-en.html

Some general info on NGF:
https://en.wikipedia.org/wiki/Nerve_growth_factor
https://selfhacked.com/blog/all-about-nerve-growth-factor-and-50-ways-to-increase-it/

More specific research in the involvement of reproductive function:

Nerve growth factor (NGF) is relatively abundant in the prostates of several species including humans.
https://sci-hub.st/https://onlinelibrary.wiley.com/doi/abs/10.1002/(SICI)1098-2744(199810)23:2%3C106::AID-MC7%3E3.0.CO;2-W

NGF regulates sertoli cell growth and prevents LPS-induced junction protein damage via PI3K/AKT/NFkB signaling
Nerve growth factor (NGF) plays an important role in reproductive and inflammatory disease. We confirmed that Sertoli cell viability, proliferation, and ATP content increased following NGF treatment.
Intercellular junctions between adjacent Sertoli cells at the blood-testis barrier (BTB) work together to regulate germ cell development and create a microenvironment for the completion of meiosis. This microenvironment protects the germ cell from harmful substances and immune system effects. These junctions, including tight junction, gap junctions, ectoplasmic specializations, and desmosomes are influenced by a variety of cytokines including ChAT, pancreatic polypeptide, GDNF, and NGF. Tighter junctions ensure development of a better microenvironment, allowing spermatogenesis to occur successfully.
One of the first growth factors to be studied, the nerve growth factor (NGF) is known to regulate inflammation. After binding to its receptor, tropomyosin receptor kinase A (TrkA), it plays a key regulatory role in the development of diseases, such as interstitial cystitis and chronic prostatitis. NGF can act on TrkA to improve the migration and tube formation of human microvascular endothelial cells through PI3K/Akt and ERK/MAPK signaling pathways, and has a regulatory effect on the angiogenesis in patients with osteoarthritis.
The BTB acts as a protector in the reproductive system. Pro-inflammatory cytokines produced during testicular inflammation can alter the permeability of the BTB, thus damaging normal spermatogenesis.
Junction proteins are very sensitive to harmful substances; thus, common toxic substances are potential threats to male fertility. When the testes are damaged by inflammation, antibiotics alone cannot completely repair them, which is why most of the patients receive inadequate therapy. NGF plays an unexpected role in luteotrophic action, ovulation induction, sperm motility maintenance, and sperm cryopreservation. NGF is an indispensable neurotrophic factor of the male reproductive system and is necessary for appropriate sperm function. It can improve sperm motility and increase the expression of testosterone; a high NGF expression was found in highly active sperms. In addition, increased NGF expression in testis could reverse fluorine-induced testicular damage in mice. Thus, NGF has considerable potential in the treatment of testicular damage caused by toxic substances.
https://www.sciencedirect.com/science/article/abs/pii/S0093691X22004253

Nerve growth factor (NGF) the classical neurotrophic factor, regulates the development and maintenance of sympathetic and sensory peripheral neurons and central cholinergic neurons. We have demonstrated that NGF could attenuate the disease progression of senescence accelerate mouse P8 (SAMP8), an age-associated Alzheimer's disease (AD) animal model, by reducing the level of amyloid-beta peptide (Abeta) generation in the brains. Surprisingly, we noticed that NGF treatment dramatically increased serum testosterone concentrations. This finding raises the possibility that NGF treatment may become a potential therapy for age-related hypogonadism.
Nasal delivery of nerve growth factor rescue hypogonadism by up-regulating GnRH and testosterone in aging male mice. NGF could enhance the sexual function, improve the quality of the sperm, and restore the fertility of aging male SAMP8 mice with age-related hypogonadism by activating gonadotropin-releasing hormone (GnRH) neuron and regulating secretion of GnRH. And NGF regulated the GnRH release through the PKC/p-ERK1/2/p-CREB signal pathway.
These results suggest that NGF treatment could alleviate various age-related hypogonadism symptoms in male SAMP8 and may be usefulness for age-related hypogonadotrophic hypogonadism and its related subfertility.
https://www.thelancet.com/article/S2352-3964(18)30307-4/fulltext

ERbeta has a vital role in NGF modulation:

17beta-estradiol modulates NGF and BDNF expression through ERB mediated ERK signaling in cortical astrocytes
Overall results demonstrate that p-ERK1/2 levels are down-regulated by ERB inhibition in at all three time points, which indicates ERK acts as a secondary molecule for E2 mediated neurotrophin modulation via ERB receptor.
It has also been shown that estradiol and neurotrophin receptor co-expression leads to convergence of their signaling pathways.
17beta estradiol, (through both ERa and ERB), contributes to the modulation of levels of neurotrophins (NGF and BDNF) and our data suggests ERB is majorly involved and responsible for cortical astrocytes cell growth, proliferation and thus play an important role in neuroprotection.
Our results suggest that the growth stimulatory effects of 17B-estradiol in astrocytes via both receptors- ERa and ERB, predominantly by ERB. On the other hand, we also observed that ERK is not playing a role in ERa and ERB mediated astrocytes cell survival.
Estradiol receptor beta (ERB) play a vital role in mediating neurotrophomodulator functions of E2. We also show that E2-mediated modulation of neurotrophins is via ERB mediated ERK signalling pathway indicating the indirect genomic action of this hormone.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=17%CE%B2-estradiol+modulates+NGF+and+BDNF+expression+through+ER%CE%B2+mediated+ERK+signaling+in+cortical+astrocytes&btnG=

NGF can be also associated to senescence, which I believe is the root of my POIS. Other studies hold some controversy though, so of course NGF involvement must be more complex than this.

In this study, we demonstrated that senescent astrocytes display a secretory phenotype known as the senescence-associated secretory phenotype (SASP), which is associated with the upregulation of various proinflammatory factors and the downregulation of neurotrophic growth factors (e.g., NGF and BDNF), resulting in a decrease in astrocyte-mediated neuroprotection and increased risk of neurodegeneration.
https://academic.oup.com/biomedgerontology/advance-article-abstract/doi/10.1093/gerona/glad278/7510769

In the central nervous system, basal forebrain cholinergic neurons require NGF for normal function. NGF is mainly produced in the cerebral cortex and hippocampus and is transported retrogradely by axoplasmic flow as a NGF/receptor complex.
In aged rats, NGF and its mRNA decrease in parallel with learning impairments. In addition, the number of neurons immunoreactive for the NGF receptor is reduced in the basal forebrain of aged rats. Chronic administration of NGF prevents this age-related deterioration of cognitive function and the shrinkage of basal forebrain cholinergic neurons. These results imply a pivotal role for NGF in maintaining these basal forebrain neurons during the aging process.
Also, the lack of NGF may affect cholinergic neurotransmission and memory aquisition, since NGF induces choline acetyltransferase activity.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Age-related+decrease+of+nerve+growth+factor-like+immunoreactivity+in+the+basal+forebrain+of+senescence-accelerated+mice&btnG=

NGF was found to induce changes in 6 genes involved in metabolic pathway, raising the possibility that NGF may modulate liver metabolism. In addition to its plausible immunosuppressive effects on monocyte chemotactic protein 1 (MCP1, also termed CCL2) and arachidonic acid metabolism, NGF was found to down-regulate CD36 in the adipocytokine signaling pathway. Intriguingly, CD36 expression is regulated by peroxisome proliferator-activated receptor signaling, which was reduced by NGF stimulation. These findings raise the possibility that NGF may also play a role in the regulation of hepatic adipogenesis and the development of fatty liver. Intriguingly, the pathway analysis of bile acid metabolism reveals that NGF down-regulated a gene encoding a bile salt export pump (BSEP), while BSEP gene depletion is more recently found to favor detoxification of potentially toxic bile acids and protect cholestatic liver injury.
https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S104346661730368X

Possible relations to other theories:
- estrogen receptor beta involvement:
https://poiscenter.com/forums/index.php?topic=4061.0
- senescence and SASP:
https://poiscenter.com/forums/index.php?topic=4321.0

[Progecitor]

Also a good list of supplements to modulate NGF. Of course many of these have been already found to be useful in the treatment of POIS (e.g. Selegiline (Deprenyl), etc.)

Hypothesized to Increase NGF
Proposed mechanisms are stated next to the substance.

These mechanisms are all hypothetical and unproven.

1. Butyrate [42]
2. PQQ – an antioxidant that is also being researched for stimulating NGF and promoting peripheral nerve regeneration [43].
3. ALCAR – claimed to increase levels of neurotrophins such as NGF [44, 45] and affect nerve regeneration in rats.
4. Rosemary (Carnosic acid) – hypothesized to induce NGF production [46].
5. Quercetin – said to promote nerve growth, and has shown the ability to regenerate peripheral nerves [47, 48].
6. Ginkgo Biloba (Has Quercetin) [49]
7. Lion’s Mane (Hericium erinaceus) – An edible mushroom that might boost NGF in animals [50].
8. Zinc – Zinc may increase NGF in animals; however, memory was improved only when Vitamin A was sufficient [51]. Zinc may also bind to NGF, blocking its effect, but is thought to be lessened under a more acidic pH in test tubes [52].
9. Vitamin D3 – The active form of vitamin D is being researched for impacting the NGF concentration in brain cells, alone or with Forskolin [53, 54].
10. Melatonin – injections increased NGF in the submandibular gland of mice at a specific dose that can’t be translated to humans [55].
11. DHEA – Might induce overproduction of NGF cortical neurons [56].
12. Astragalus – The extract may act as a nerve-growth promoting factor [57].
13. Huperzine A – An alkaloid from herbs that seems to boost NGF in animals [58].
14. Bupleurum (Chinese herb Radix Bupleuri) – Raises blood levels of NGF in animals [59].
15. Chrysin – A flavonoid found in honey and some plants, it increases NGF [11].
16. Royal jelly – Topically, royal jelly increases NGF in animals [60, 61].
17. Rehmannia – Improves learning and memory in rats, possibly due to increased NGF in the hippocampus [62].
18. Polygala tenuifolia – The root extract (used in Chinese Medicine) increased NGF in the lab [63].

Hypothesized to Support NGF Activity:

1. Green Tea/EGCG – Green tea polyphenols increase NGF-induced nerve growth in animals. EGCG is hypothesized to enhance NGF-induced neuronal growth [64, 65].
2. Milk Thistle [66]
3. DHA (NGF induced neuronal growth) [67, 68].
4. Vitamin A (via increased NGF receptors and sensitizing cells to the effects of NGF) [69]
5. Phosphatidylserine – thought to protect receptors. PS helps older rats retain more quality neurons and a higher density of NGF receptors [70].
6. Gotu Kola (Centella asiatica) – (neurite outgrowth in the presence of NGF) [71]
7. Alpha-GPC (choline alfoscerate) – May increase the expression of NGF receptors in the brain [72].
8. Uridine + Choline + DHA – Feeding omega-3s (DHA or EPA) to gerbils eating a choline-rich diet improved the nerve membranes, especially when also given with a dietary source of uridine [73]. This combination seemed to improve performance. Scientists are investigating whether [74, 75] uridine converts to a form of choline called GDP-choline when it enters the brain [76]. Uridine Monophosphate (rich in foods such as organ meats, brewer’s yeast, tomatoes, and broccoli) may release uridine in the gut.
9. Forskolin [77]
10. Genistein [78]
11. Nardosinone (from Chinese spikenard) [79, 80]
12. 4-O-methylhonokiol – A compound from Magnolia officinalis [81]

Hormones and Drug Pathways (Experimental)

1. Estrogen
2. Progesterone

Additionally, scientists found links between the following drugs and higher NGF levels in animals:

1. Idebenone [83, 84] – Thought to stimulate NGF, antioxidant properties have been disputed [83].
2. Selegiline (drug) – A metabolite of Selegiline, desmethylselegiline, theorized to elevate NGF, BDNF, and GDNF [85].
3. 2-deoxy-D-glucose (2-DG) – A compound suspected to produce ketones. 2-DG significantly increased expression of NGF in mice [86].
4. Prescription lithium – increased NGF in specific parts of the brain: frontal cortex, amygdala, hippocampus, and limbic forebrain in adult rats [87].
5. NGF eye drops (highly controversial and unproven) [88].
6. “Nicotine”
7. “Noopept”

https://selfhacked.com/blog/all-about-nerve-growth-factor-and-50-ways-to-increase-it/