35 replies to this topic

[gamesguru]

First off, much credit is owed to Flex, who basically wrote the dopamine D2 section, and to Area, who basically wrote the 5-HT2A/5-HT6 section.

I'm continuing my series of threads on naturally treating serious mental conditions. This time my approach is to try to emulate pharmaceutical mechanisms with OTC herbs.

• Abilify: D2 agonist
• Flouxetine: SSRI, 5-HT2C agonist
• Citalopram: SSRI
• Olazapine: D2, 5-HT2A and 5-HT6 antagonist
• Sumatriptan: 5-HT1B and 5-HT1D agonist
• Amitriptyline: D2, 5-HT2A, 5-HT7 antagonist, NMDAR antagonist, sodium channel blocker
• Valproate: Sodium channel blocker

Lithium helps both bipolar and borderline[!] disorders. It's available in orotate form on Amazon, most common is the Swanson brand.
I'm recommending 1.25mg for borderline and 2.5mg for bipolar. You can lower this slightly, if you drink mineral water, eat certain foods, or exhibit symptoms of lithium sensitivity or toxicity.

Then a low sodium diet [!].  The reason for this overlaps with antiepileptic drugs treating bipolar, which are all sodium channel blockers. Sodium channels are involved in glutamate cascades.  A ketogenic diet also appears helpful[!], but this may not help in the case of a low sodium diet, as the ketogenic diet appears helpful due to blood acidification and subsequent desalination.  A high tryptophan and low tyrosine diet appears helpful.
 

Mania

• Magnesium, citicoline, phosphatidylcholine or-serine, and folate may help treat mania.

Depression

• Omega-3s, chromium, calcium, zinc, and perhaps inositol
• Vinpocetine and Reserpine, an alkaloid derivative of Rauwolfia serpentina, both VMAT inhibitors
• Rhodiola may be tested as an adjuctive antidepressant in cases of low energy or chronic fatigue.
• ALCAR/PS
• to be completed...

====
Site
====

Pharm: site action

• herbals

 

 

===========
Dopamine D2

===========

Abilify: D2 agonist

 

D2 agonists

• Corydalis yanhusuo [1]
• Cimicifuga racemosa and Vitex agnus cactus [2]
• Peony-Glycyrrhiza Decoction (glycyrrhetinic acid, watch out for antiandrogen effects [!]) [3]
• Salvinorin A [4]
• Sangorine [5]

Misc D2 agents

• Low homocysteine diet (D2 negative allosteric modulator) [1a] [1b]

=====
SERT
=====

Citalopram: SSRI

• Bacopa [1a] [1b] [1c] [1d]
• St. John's Wort (also boosts PFC dopamine) [2]
• Saffron [3]
• Curcumin [4]

 

======================
Serotonin, including 5-HT6
======================

Olazapine: 5-HT2A and 5-HT6 antagonist [!]

• Magnolia officinalis (5-HT6 antagonist) [1]
• Skullcap (5-HT7 antagonist) [2]

1A/2A antagonist and 1B agonist.  See [1], [2] and [3]

• Ginkgo (5-HT1A antagonist) [1a] [1b] [1c]
• Nantenine (5-HT2A and α₁ antagonist) [2]
• Ergotamine (5-HT1B agonist) [3]

=================
NMDAR hypofunction
=================

Valproate, lamictal, carbamazepine: sodium channel blockers

Sodium Channel Blocker

• lappaconitine [1a] [1b]

Glutamate release inhibitors

• Bromocriptine (also a D2 agonist) [1]
• Curcumin [2]
• note: green tea EGCG evokes a minor glutamate release, and might be expected to worsen mania

Glutamate antagonists

• Kaitocephalin [1]
• Ibogaine [2]
• Ketamine
• Memantine

Presynaptic GABA antagonists

• Ginkgo (also glycine antagonist) [1]
• Ginseng (GABA_A and GABA_B) [2a] [2b]

Akt and TrkB affect glutamate release

• Tenuifoliside A (TrkB activator) [1]
• Psoralidin (Akt inhibitor) [2]
• Lithium (TrkB actiavator, Akt and mGlur5 inhibitor) [3a] [3b] [3c]

GLDH Inhibitors

• Radix scutellariae [1]
• Radix codonopsis
• Radix paeoniae alba

Final recommendation: a low glutamine diet, with something clever to stimulate GAD (taurine?), or a small maintenance dose of GABA, picamilon, or theanine.

[normalizing]

interesting, informative thank you. i have a question about the d2 agonists, do these actually stimulate dopamine release or how do they work exactly because the explanation on wiki was not very user friendly for me. im actually interested in natural dopamine stimulators, releasers, any clue to compile a list? or i assume d2 agonists are just what fills my interest here.

[gamesguru]

its sort of a double-edged sword, because striatal hyperdopamine AND frontal hypodopamine are implicated in schizorphenia.  the former in negative symptoms, the latter in positive.

the problem with medicines, is we cant tell them to go only to the striatum or frontal cortex, they diffuse relevately evenly across all brain regions.

if you check the literature youll find this trend: D2 agonists treat negative symptoms (in the mPFC) and D2 antagonists treat positive symptoms (in the striatum).

 

i bypassed this issue by ignoring positive symptoms, which greatly simplifies the problem.

by only considering negative symptoms, the solution is reduced to D2 agonists (in the mPFC)

 

 

 

D2 agonists just increase receptor activity to nearer baseline. D2 is implicated in BDNF, GABA, glutamate. generally understimulation of D2 causes excitotoxicity, but overstimulation can be just as bad. and a major problem in schizoprhenia is cell death, glutamatergic and dopaminergic excitotoxicity. so by reducing cell death/excitotoxicity and modulating BDNF, you do a lot to restore a healthy state.

 

btw what fills your interest if you are concerned with blunted affect are largely the strategies to reduce glutamate, because again pointing the finger to excitotoxicity, hyperglutamatergic cell death is a major cause of reduced social cognition, increased social anhedonia, and difficulty recognizing and wearing facial expressions. and you cant solve this hyperglutamatergic state just with D2 agonists, or at least i wish you the best of luck in such an endeavor.

[normalizing]

i want to enhance dopamine as i believe i have really downregulated or damaged the system with abuse of alcohol and dopaminergic stimulants in the past. what you speak of about social cognition and all aspect of social interactions are hard for me now because of it but also it could be due to glutamate toxicity too related to alcohol. in simple idea i just hope to somehow balance or even better increase dopamine production but as it seems something to do with glutamate long term toxicity might be just as a good idea

[gamesguru]

For enhancing dopamine, I give some options in my schizotypy thread. Ginkgo, ginseng and green tea all act as DRIs, bacopa prevents some forms of dopamine depletion, and I'm sure Flex could chime in with 10 other herbs.  He and I recently looked into some natural dopamine antagonists, so if the agonist route backfires we have a plan B.  Also for dopamine:

• COMT inhibitors
• VMAT inhibitors (in moderation)
• DBH inhibitors
• DOPA decarboxylase promoters
• dietary tyrosine

For glutamate,

• PKC inhibitors (those also have a role in dopamine [1])
• theanine reduces glutotoxicity
• curcumin inhibits mPFC glutamate release
• low glutamic acid diet
• small dose supplemental GABA
• Lactobacillus rhamnosus[!]

To repair damage already done, I'm thinking neurotrophins (NGF, BDNF, GDNF, bFGF), in which case I got you somewhat covered bro:

 

http://www.braintrop...h-factor-stack/ (this guy claims the best NGF stack. any guy who claims that, you gotta lend him your ear)

http://www.longecity...st/#entry746270 (AHN = adult hippocampal neurogenesis)

http://www.longecity...s-into-neurons/

http://www.longecity...-neural-growth/

 

http://www.longecity...-increase-bdnf/

 

http://www.longecity...ogenesis-in-it/

http://www.longecity...frontal-cortex/

 

 

(this is an idea borrowed from the last thread, on the prefrontal cortex [mPFC])

Any TrkB agonist or antagonist (dihexa, 7,8-dihydroflavone)

Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist.

LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc.

Edited by gamesguru, 30 March 2016 - 01:08 AM.

[normalizing]

as usual, very informative and interesting from you. attention well paid!

just to mention from past experience, tyrosine and phenylalanine used to work and be quite potent too for such easy to obtain legal simple supplements but now days even megadoses of the stuff wont even give a hint of what it did back then indicating that damage has been done and probably irreversible. :/

but i will look into those other suggestions, again, thank you very much

[gamesguru]

Too much tyrosine will downregulate D2 receptors, autoreceptors, and tyrosine hydroxylase (TH).  Left untreated, it will elevate norepinephrine levels and wreak havoc on your hind- and forebrain.

iirc, horny goat weed is good for restoring TH. see this thread: http://www.longecity...ne-hydroxylase/

 

and if you got downregulated dopamine receptors/autoreceptors you actually want dopamine antagonists, negative allosteric modulators, uptake enhancers, release inhibitors, inhibitors of synthesizing enzymes and promoters of degradatory enzymes, and a low tyrosine high tryptophan diet. it would be overkill to go from all angles, so pick one or two, as well as focusing on TH, see this thread: http://www.longecity...ne-hydroxylase/

 

heres info on dopamine antagonists

5-HT2C agonists

1) Astonine

2) N-3′-ethylaplysinopsin and 6-bromo-2'-de-N-methylaplysinopsin (marine indole alkaoids)

 

apigenin is negative modulator on GABA_A...

 

Rest are antagonists:

Ginkgo (GABA_A & 5-HT_1A), Dicyma sp (GABA_A), ginseng (GABA_B), Ziziphus (5HT_1B), Nandina Domestica/isorhynchophylline/Gramine/Puerarin(5-HT_2A), Magnolia and Bacopa (5-HT₆), Rikkunshito/Prozac/SB-242084 (5-HT_2C), gleditsioside F (D1), L-stepholidine (D2), 5-Hydroxy-indoline of Phoebe chekiangensis (D4)

 

 

here's a thread, 'Wingless' complains of the same problem

http://www.longecity...ptor-densities/

 

this one i make state some controversial opinions

http://www.longecity...mphetamine-use/

[normalizing]

N-3′-ethylaplysinopsin and 6-bromo-2'-de-N-methylaplysinopsin (marine indole alkaoids) - confusion on these, never heard of them and wiki is unfriendly on this...

[gamesguru]

6-bromo is also doubly antioxidative, being able to donate two electrons and two H atoms[1]

N-3' apparently has antiviral/antibiotic/antiparasitic effects (see studies [5] and [6])

im sure theyre good for other things too

 

heres a few studies summarizing what we know about marine indoles

• "their potential affinity to various neurological targets" [2]
• "specific biological activities including cytotoxicity, antiviral, antiparasitic, serotonin antagonism and other pharmacological activities of sixty-nine bis and trisindole alkaloids" [3]
• semisynthetic modification of marine natural products, with the emphasis on compounds possessing activity against infectious diseases, cancer, and neuropsychiatric disorders... synthesis of potential antidepressant and anxiolytic drug leads from marine invertebrates" [4]
• "Aureol N,N-dimethyl thiocarbamate (1a) and 6-bromoaplysinopsin (7) exhibit significant antimalarial and antimycobacterial activity in vitro. Compound 6 showed activity against the Plasmodium enzyme plasmepsin II. The 6-bromo-2'-de-N-methylaplysinopsin (6), 6-bromoaplysinopsin (7), and N-3'-ethylaplysinopsin (9) displaced high-affinity [(3)H]antagonist ligands from cloned human serotonin 5-HT(2) receptor subtypes, whereas the other compounds tested did not. Remarkably, the 6-bromo-2'-de-N-methylaplysinopsin (6) showed a > 40-fold selectivity for the 5-HT(2C) subtype over the 5-HT(2A) subtype" [5]
• Two new prenylated indole alkaloids, 17-epi-notoamides Q and M (1 and 2), and two new phenyl ether derivatives, cordyols D and E (9 and 13), together with 10 known compounds (3–8, 10–12, 14) were isolated from a marine-derived Aspergillus sp. fungus... The polybromide phenyl ether 14g showed pronounced antibacterial activity against Staphylococcus epidermidis with an MIC value of 0.556 μM, stronger than that of the positive control ciprofloxacin [6]

[normalizing]

thanks, thats interesting. but its new and novel and unexplored as of yet. i doubt such things will be on the market in the next 10 years or so...

[gamesguru]

not as though these lab synths will be widely available sooner.

 

do a startup, bring them to the market, ill write your blog and help advertise

Edited by gamesguru, 02 April 2016 - 05:43 PM.

[sativa]

Another potent neurotrophic: Synaptolepis kirkii.

Kirkii is traditionally used by the Zulu and Xhosa to induce spiritual visions, trances and dreams. "Uvuma-omhlope" encourages mental clarity and very deep dream states.

I recently acquired various oneirogens to "explore dreaming" and kirkii root was the first one I tried. It enhanced dream sequences, recall and overall clarity. I wake up feeling refreshed, similarly to the effect of Theanine when taken before sleep, Theanine also promotes BDNF and I believe GDNF.

Neurotrophic and antileukemic daphnane diterpenoids from Synaptolepis kirkii

Abstract
Biological assay guided fractionation of a dichloromethane extract of Synaptolepis kirkii led to the isolation of four new and five known daphnane-type diterpene orthoesters, whose structure was established by spectroscopic data. Full spectroscopic data of the new and known natural products are reported here for the first time. Pronounced neurotrophic and substantial antileukaemia activities of these compounds were found in in vitro assays.

http://www.ncbi.nlm....pubmed/12150870

-

Kirkinine, a new daphnane orthoester with potent neurotrophic activity from Synaptolepis kirkii.

Abstract
The bioassay-guided fractionation of a dichloromethane extract from the roots of Synaptolepis kirkii using neuronal viability as a model allowed the isolation of the new daphnane orthoester kirkinine (1a) as a powerful neurotrophic constituent.

http://www.ncbi.nlm....pubmed/11000015

With regards to dopamine enhancement, I use (or ensure I have sufficient amounts of) the following things:

Niacin, NAC, B9, manganese, magnesium

Blue lotus is a D2 agonist I believe, I'm not sure whether it applies to D2 long or short...

Edited by sativa, 03 April 2016 - 07:33 PM.

[gamesguru]

its my first time hearing of kirkii.

you think the sleep/dream properties have to do with neurotrophins?

then would lions mane, turmeric and royal jelly make a good dreaming stack?

The homeostatic regulation of REM sleep: A role for localized expression of BDNF in the brainstem.

 

Dreaming and REM Sleep

 

Cannabis, catecholamines, rapid eye movement sleep and aggressive behaviour.

 

Sleep Disturbance in Heavy Marijuana Users

The orbitofrontal cortex is a brain region of special interest (also involved in borderline personality's sleep disturbances). Discontinuation of MJ use and difficulty initiating and maintaining sleep are associated with decreased [glucose] metabolism in the OFC^24,30 and acute administration of THC increases OFC metabolism,³² which may alleviate insomnia. This mechanism may explain the propensity to relapse after a short abstinent period.

• BDNF Stimulates Energy Metabolism in Developing Cortical Neuron
• BDNF regulates glucose metabolism by modulating energy balance in diabetic mice.

[normalizing]

Another potent neurotrophic: Synaptolepis kirkii.

Kirkii is traditionally used by the Zulu and Xhosa to induce spiritual visions, trances and dreams. "Uvuma-omhlope" encourages mental clarity and very deep dream states.

I recently acquired various oneirogens to "explore dreaming" and kirkii root was the first one I tried. It enhanced dream sequences, recall and overall clarity. I wake up feeling refreshed, similarly to the effect of Theanine when taken before sleep, Theanine also promotes BDNF and I believe GDNF.
 

Neurotrophic and antileukemic daphnane diterpenoids from Synaptolepis kirkii

Abstract
Biological assay guided fractionation of a dichloromethane extract of Synaptolepis kirkii led to the isolation of four new and five known daphnane-type diterpene orthoesters, whose structure was established by spectroscopic data. Full spectroscopic data of the new and known natural products are reported here for the first time. Pronounced neurotrophic and substantial antileukaemia activities of these compounds were found in in vitro assays.

http://www.ncbi.nlm....pubmed/12150870

-

Kirkinine, a new daphnane orthoester with potent neurotrophic activity from Synaptolepis kirkii.

Abstract
The bioassay-guided fractionation of a dichloromethane extract from the roots of Synaptolepis kirkii using neuronal viability as a model allowed the isolation of the new daphnane orthoester kirkinine (1a) as a powerful neurotrophic constituent.

http://www.ncbi.nlm....pubmed/11000015

With regards to dopamine enhancement, I use (or ensure I have sufficient amounts of) the following things:

Niacin, NAC, B9, manganese, magnesium

Blue lotus is a D2 agonist I believe, I'm not sure whether it applies to D2 long or short...

 

 

 

to comment on your "dopamine enhancement" suggestion, no offense but i find it absolutely ridiculous. ive taken all of those in high doses for various reasons in the past all at once or separately and not only did they not help for the reasons i was taking them originally, but absolutely definitively did not help even slightly for anything related to dopamine.

 

now, im curious about lotus's D2 agonism as i have seen this mentioned in medical texts before. does it work as antipsychotic and is it detrimental like all other pharm sold antipsychotics or is it just too weak to have any benefit or negative effects short or long term?

 

 

edit: i spent some time trying to find info on synaptolepis and its just one report repeating itself as if done by one person. sources are scarce. for example, NCBI has only 4 outdated articles done by belgium people; http://www.ncbi.nlm....ptolepis kirkii

 

 

Edited by normalizing, 04 April 2016 - 08:05 AM.

[sativa]

With regards to dopamine enhancement, I use (or ensure I have sufficient amounts of) the following things:

Niacin, NAC, B9, manganese, magnesium

Blue lotus is a D2 agonist I believe, I'm not sure whether it applies to D2 long or short...

to comment on your "dopamine enhancement" suggestion, no offense but i find it absolutely ridiculous. ive taken all of those in high doses for various reasons in the past all at once or separately and not only did they not help for the reasons i was taking them originally, but absolutely definitively did not help even slightly for anything related to dopamine.

now, im curious about lotus's D2 agonism as i have seen this mentioned in medical texts before. does it work as antipsychotic and is it detrimental like all other pharm sold antipsychotics or is it just too weak to have any benefit or negative effects short or long term?

Well, apart from NAC, those substances are dopamine prerequisites from what I gather and so any deficiency would negatively impact dopamine production.

Re blue lotus's D2 activity, I will find out more info and post it asap.

Regarding Reserpine, it "irreversibly blocks the vesicular monoamine transporter (VMAT)" meaning the body has to regenerate VMAT's. In the meantime, this means reduced neurotransmitter circulation/availability (AFAIK)

Edited by sativa, 04 April 2016 - 09:12 AM.

[sativa]

The memory-enhancing effects of Euphoria longan fruit extract in mice.

Abstract
AIM OF THE STUDY: The fruit of Euphoria longan (Lour.) Steud. (Sapindaceae) is sweet and edible. Dried Euphoria longan fruit is prescribed as a tonic and for the treatment of forgetfulness, insomnia, or palpitations caused by fright in traditional Chinese medicine. The effects of aqueous extract of Euphoria longan fruit (ELE) on learning and memory and their underlying mechanisms were investigated.

MATERIALS AND METHODS:
Aqueous extract of Euphoria longan fruit (ELE) was administered to ICR mice for 14 days. Piracetam was used as a positive control for its known memory-enhancing effects. Memory performances were assessed using the passive avoidance task. The expressions of phosphorylated extracellular signal-regulated kinase (pERK) 1/2, phosphorylated cAMP response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), doublecortin (DCX) and the incorporation of 5-bromo-2-deoxyuridine (BrdU) in hippocampal dentate gyrus and CA1 regions were investigated using immunohistochemical methods.

RESULTS:
The step-through latency in the ELE-treated group was significantly increased compared with that in the vehicle-treated controls (P<0.05) in the passive avoidance task. Piracetam-treated group also showed enhanced cognitive performaces in the passive avoidance task. Immunohistochemical studies revealed that the number of cells immunopositive for BDNF, pCREB, or pERK 1/2 was significantly increased in the hippocampal dentate gyrus and CA1 regions after ELE treatment for 14 days (P<0.05). DCX and BrdU immunostaining also revealed that ELE significantly enhanced immature neuronal survival, but not neuronal cell proliferation in the subgranular zone of the dentate gyrus.

CONCLUSIONS:
The present results suggest that subchronic administration of aqueous extract of Euphoria longan fruit enhances learning and memory, and that its beneficial effects are mediated, in part, by BDNF expression and immature neuronal survival.

www.ncbi.nlm.nih.gov/pubmed/20064595

Edited by sativa, 05 April 2016 - 10:32 AM.

[sativa]

BDNF up-regulates alpha7 nicotinic acetylcholine receptor levels on subpopulations of hippocampal interneurons.

Abstract:
In the hippocampus, brain-derived neurotrophic factor (BDNF) regulates a number of synaptic components. Among these are nicotinic acetylcholine receptors containing alpha7 subunits (alpha7-nAChRs), which are interesting because of their relative abundance in the hippocampus and their high relative calcium permeability. We show here that BDNF elevates surface and intracellular pools of alpha7-nAChRs on cultured hippocampal neurons and that glutamatergic activity is both necessary and sufficient for the effect. Blocking transmission through NMDA receptors with APV blocked the BDNF effect; increasing spontaneous excitatory activity with the GABA(A) receptor antagonist bicuculline replicated the BDNF effect. BDNF antibodies blocked the BDNF-mediated increase but not the bicuculline one, consistent with enhanced glutamatergic activity acting downstream from BDNF. Increased alpha7-nAChR clusters were most prominent on interneuron subtypes known to directly innervate excitatory neurons. The results suggest that BDNF, acting through glutamatergic transmission, can modulate hippocampal output in part by controlling alpha7-nAChR levels.

www.ncbi.nlm.nih.gov/pubmed/17029981

[sativa]

Rapid Antidepressant Activity of Ethanol Extract of Gardenia jasminoides Ellis Is Associated with Upregulation of BDNF Expression in the Hippocampus.

Abstract

Ethanol extract of Yueju pill, a Traditional Chinese Medicine herbal formula widely used to treat mood disorders, demonstrates rapid antidepressant effects similar to ketamine, likely via instant enhancement of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Here we investigated ethanol extracts of the constituent herbs of Yueju responsible for rapid antidepressant effects. Screening with tail suspension test in Kunming mice at 24 hours after a single administration of five individual constituent herbs of Yueju, we found that only Gardenia jasminoides Ellis (GJ) showed a significant effect. The antidepressant response started at 2 hours after GJ administration. Similar to Yueju and ketamine, a single administration of GJ significantly reduced the number of escape failures in the learned helplessness test. Furthermore, GJ decreased latency of food consumption in the novelty suppressed-feeding test. Additionally, starting from 2 hours and continuing for over 20 hours after GJ administration, BDNF expression in the hippocampus was upregulated, temporally linked with the antidepressant response. These findings suggest that GJ has rapid antidepressant effects, which are associated with the elevated expression of BDNF in the hippocampus. In Yueju formula, Yue represents GJ, as thus our study demonstrates the primary role of GJ in rapid antidepressant efficacy of Yueju.

http://www.ncbi.nlm....pubmed/25878718

[sativa]

Oroxylin A is an O-methylated flavone, a chemical compound that can be found in the medicinal plant Scutellaria baicalensis[1] and the Oroxylum indicum tree.[2] It has demonstrated activity as a dopamine reuptake inhibitor,[3] and is also a negative allosteric modulator of the benzodiazepine site of the GABAA receptor.[3][4][5]

Oroxylin A has been found to improve memory consolidation in mice by elevating brain-derived neurotrophic factor (BDNF) levels in the hippocampus.[6]

Source wikipedia Oroxylin A page

Edited by sativa, 25 April 2016 - 04:23 PM.

[sativa]

www.nature.com/articles/srep05555

Protective Effect of Dl-3n-butylphthalide on Learning and Memory Impairment Induced by Chronic Intermittent Hypoxia-Hypercapnia Exposure

...
Dl-3n-Butylphthalide (NBP), extracted from Apium graveolens Linn, has displayed a broad spectrum of neuroprotective properties.

Our study aimed to investigate the potential of NBP on CIHH-induced cognitive deficits. The cognitive function of rats after CIHH exposure was evaluated by the Morris water maze, which showed that the NBP treated group performed better in the navigation test.

NBP activated BDNF and phosphorylated CREB, the both are responsible for neuroprotection. Additionally, NBP decreased CIHH induced apoptosis. Moreover, NBP further induced the expression of HIF-1α, accompanied by the up-regulation of the autophagy proteins Bnip3, Beclin-1 and LC3-II.

Finally, NBP also reversed the decreased expression of SIRT1 and PGC-1α, but the expression of Tfam, Cox II and mtDNA remained unchanged.

These results suggested that the neuroprotective effects of NBP under CIHH condition possibly occurred through the inhibition of apoptosis, promotion of hypoxia-induced autophagy, and activation of the SIRT1/PGC-1α signalling pathway, while stimulation of mitochondrial biogenesis may not be a characteristic response.

Edited by sativa, 26 April 2016 - 08:47 AM.

[gamesguru]

I feel as though sativa is directing too much attention to BDNF, getting on sort of a "BDNF tangent".  

 

What about HGF, inflammatory cytokines, snyaptophysin, other neurtransmitters and neuropeptides, the mitochondria and endoplasmic reticulum?  Surely the list goes on?

Let's look at HGF, which is what makes Dihexa special.

Although a number of creative and successful approaches in animal models have been employed to deliver growth factors like GDNF (Wang et al., 2011) to the brain, these methodologies are technically complex and prohibitively difficult to bring to practice with large numbers of patients.  While many growth factor systems have been examined as potential therapeutic targets for Parkinson’s disease (PD) one that has been largely, and we think mistakenly, overlooked is the hepatocyte growth factor (HGF)/c-Met (its type I tyrosine kinase-receptor) system…

 

In fact, HGF plays a role in many common psychiatric conditions

•  “These results suggest an association between low HGF levels, schizophrenia and bipolar disorder and also demonstrate that zinc therapy may be associated with the normalization of HGF levels and decrease in severity of disease.”
• “These results suggest an association between HGF and GABA levels and suggest that plasma GABA levels are related to symptom severity in autistic children.”
• “These results suggest an association between HGF serum levels and clinically depressed individuals and demonstrate a correlation between severity of depression and HGF levels. Further studies of the predictive strength of HGF as a biomarker for depression may be warranted.”

Interestingly, the decline of HGF function with age may be associated with a reduction of risk of "primary brain tumor" development, or the development of a brain tumor before metathesis or a tumor which BEGAN in the brain and was not planted there from another cancerous organ.  Alternatively, this trend or "dip" may be explained by increased mortality from non-brain organs in the elderly (leaving less statistics to report on brain-related fatalities).

 

 

It's worth noting that several common substances inhibit the synthesis or HGF or supress phosphorylation of c-MET receptor.

These common substances may therefore be bad for disease-states.  While I am not recommending you cut out all dietary sources, may pay attention to rich sources, and limit the intake of those foods in your diet?

 

Suppressors of HGF or c-MET

• Quercetin [1] (this one is really common in most diets)
• Luteolin [2] (this one is somewhat common)
• Pasqueflower [3]
• Penicillium chrysogenum [4]

 

As for increasing c-MET activity, zinc has already been suggested [!].

 

Naringin and hesperidin, two naturally-occurring flavonoids, may have c-MET stimulating properties, in this respect they resemble Dihexa.  They may increase risk of brain cancer, in this respect, they also resemble Dihexa.  It would be interesting to see studies evaluating these two flavonoids (or Dihexa for that matter) in the treatment of borderline or bipolar (or typical depression).  Then, forgoing and excluding other effects or mechanisms, we could make conclusions about the role of HGF deficiency in psychiatric conditions.

Specifically, naringin and hesperidin induced the greatest migratory response... [!]

Edited by gamesguru, 29 April 2016 - 05:19 PM.

[sativa]

I feel as though sativa is directing too much attention to BDNF, getting on sort of a "BDNF tangent".

That's true, I was mainly just posting my BDNF findings here to spread the word and it seemed relevant! Perhaps they are more relevant to the "natural ketamine" thread (http://www.longecity...for-depression/)

Edited by sativa, 29 April 2016 - 06:06 PM.

[normalizing]

gamesguru, from what i see HGF has a lot to do with cancer either stimulate or prevent it depending on inhibition or stimulation, is this really a good target to mess around with for some proposed brain benefits? the substances you post that block it are actually shown to prevent cancer so that is not necessary bad to use them. and the naringenin and hesperidin dont seem such good guys if they actually promote HGF...

 

btw i couldnt find references to naringenin and hesperidin having anything to do with HGF, pinpoint?

Edited by normalizing, 29 April 2016 - 09:04 PM.

[gamesguru]

That's true, I was mainly just posting my BDNF findings here to spread the word and it seemed relevant! Perhaps they are more relevant to the "natural ketamine" thread (http://www.longecity...for-depression/)

perhaps such a thorough investigation deserves its own topic, e. g. http://www.longecity...-increase-bdnf/ and http://www.longecity.org/forum/topic/52921-best-supplements-to-stimulate-neurotrophic-factors/

it's also worth nothing that increased BDNF isn't always good, in fact higher levels are associated with ADHD [1, 2] autism [3], bipolar [4], and schizophrenia [5]

 

 

gamesguru, from what i see HGF has a lot to do with cancer either stimulate or prevent it depending on inhibition or stimulation, is this really a good target to mess around with for some proposed brain benefits? the substances you post that block it are actually shown to prevent cancer so that is not necessary bad to use them. and the naringenin and hesperidin dont seem such good guys if they actually promote HGF...

 

btw i couldnt find references to naringenin and hesperidin having anything to do with HGF, pinpoint?

we need further research to assess the significance of the increased incidence of cancer, it could be negligible or quite severe.  perhaps the elderly or the nutritionally-challenged could benefit from a modest dose of Dihexa, but sure youre right, large doses in the healthy long-term are concerning.  youll find theres always a tradeoff with supplements, no miracle herb so to speak.  everything has unintended consequences, downstream, or through a secondary mechanism.  dirty pharmacology so to speak.  perhaps in this case dietary factors and exercise to offset any increased risk of cancer, and thus justify the whole regimen.

 

i said they may have c-MET stimulating properties, and that's only been suggested by the result of a study indicating increased migration of cancer cells (which isnt a guarantee on anything HGF-promotion related)

it's also worth noting that angiostatins (roughly opposite in action to angiotensins, which Dihexa is an angiotensin IV derivative) generally have anticancer effects, through inhibiting angiogenesis.

 

green tea inhibits VEGF [1], and this is thought to underlie much of its anticancer effect [!]

the same goes for lutein and PDGF [2], inhibition of which is also antitumorigenic [!]

Edited by gamesguru, 04 May 2016 - 07:12 PM.

[birthdaysuit]

Hey, Gameguru it would be awesome maybe in the future if you did a section on IDO inhibitors or herbs and supplements that can inhibit the production of Quinolinic acid.

[gamesguru]

Hey everyone, obvious omission is obvious.  (Red) ginseng is potent D2 agonist.

 

As per, IDO & Quinolinic acid:

• Alpha-methyl-tryptophan
• Pyruvate
• Rosmarinic acid
• Norharmane
• COX-2 inhibitors, such as ginger

with further attention to be paid to: Kynurenine pathway, JAK2 inhibition, and pyridine analogs of quinolinic acid.

[birthdaysuit]

Hey everyone, obvious omission is obvious.  (Red) ginseng is potent D2 agonist.

 

As per, IDO & Quinolinic acid:

• Alpha-methyl-tryptophan
• Pyruvate
• Rosmarinic acid
• Norharmane
• COX-2 inhibitors, such as ginger

with further attention to be paid to: Kynurenine pathway, JAK2 inhibition, and pyridine analogs of quinolinic acid.

Would taking D2 agonists like ginseng for long-term lead to a down regulation of D2 receptors or is this not the case?

 

And in the case of blocking JAK2 and IDO, would there be anything that doesn't block IFN-y, IL-6 and IL-12? 

 

 

[gamesguru]

You're right, it does have a slight rebound effect.  But generally it's very mild and clears very quickly compared, as a reference, to DA desensitization from drug abuse.  Further, some conditions are characterized by too many presynaptic receptors, in this way, a low dose of ginseng could selectively downregulae presynaptic autoreceptor sites, and increase overall DA release.  That's how SSRIs work, and why their effects are delayed a few weeks.

 

Not sure what the concern is here, but IL-6 has more inflammatory than antiinflammatory properties, inhibiting it is even good for arthritis.  Rosmarinic acid seems to be relatively inactive across interferons and interluekins, so whatever your concern, this is a good choice.  It also acts as an AGE blocker (very potent) and a weaker releaser of GABA (GABA-T inhibition).  It's also one of the two mentioned supplements that it's widely available, ginger being the other.

[birthdaysuit]

You're right, it does have a slight rebound effect.  But generally it's very mild and clears very quickly compared, as a reference, to DA desensitization from drug abuse.  Further, some conditions are characterized by too many presynaptic receptors, in this way, a low dose of ginseng could selectively downregulae presynaptic autoreceptor sites, and increase overall DA release.  That's how SSRIs work, and why their effects are delayed a few weeks.

 

Not sure what the concern is here, but IL-6 has more inflammatory than antiinflammatory properties, inhibiting it is even good for arthritis.  Rosmarinic acid seems to be relatively inactive across interferons and interluekins, so whatever your concern, this is a good choice.  It also acts as an AGE blocker (very potent) and a weaker releaser of GABA (GABA-T inhibition).  It's also one of the two mentioned supplements that it's widely available, ginger being the other.

 

Awesome, so I'll continue to take Ginseng then. And the reason I do not want to suppress IL-12 and various other inflammatory responses is because I have multiple systemic infections. I know anti-inflammatories help with Lyme induced arthritis but decreased IL-10 leads to less spirochete load, whereas elevated IL-10 helps with arthritic symptoms but also can lead to a more malignant and disseminated infection.

 

Moreover, I believe Rosmarinic acid disrupts the tyroid. Heard it can increases Hypo tendencies but I've also read studies that it has amphithyroid qualities, so I don't know? It very well could excite hypoactive and depress hyperactive thyroids, but in my case drinking lemon balm tea and taking lemon balm supplements led to Hypothyroidism.

 

I'm going to stick with ginger, though.

 

[gamesguru]

Forgot about your lyme, and I didn't know that about it.

 

Bacopa also "disrupts" the thyroid, but in the positive direction.  Maybe the two would cancel out?  Either way, lemon balm is supposed to be very mild on the thyroid, so you must already be on the low side.  Same probly goes for rosemary.  And fwiw, the thyroid effects of bacopa have never been overwhelming for me, even at 600mg daily.  Currently doing 150mg

 

COX-2 and PGE2 signaling is essential for the regulation of IDO expression by curcumin in murine bone marrow-derived dendritic cells.
Jung ID1, Jeong YI, Lee CM, Noh KT, Jeong SK, Chun SH, Choi OH, Park WS, Han J, Shin YK, Kim HW, Yun CH, Park YM. (2010)

Indoleamine 2,3-dioxygenase (IDO), a key enzyme that catalyzes the initial, rate-limiting step in tryptophan degradation, is expressed in dendritic cells (DCs) which are stimulated by lipopolysaccharide (LPS) or interferons. In this study we show that curcumin inhibits IDO expression in vitro and in vivo in DCs, leading to the suppression of LPS-induced DC maturation. The effect of curcumin relative to LPS is not limited to the above, as it also enhances LPS-induced expression of cyclooxygenase (COX)-2 and production of prostaglandin E2 (PGE2). Additionally, PGE2 diminished the LPS-induced IDO expression in DCs, thereby contributing to the inhibition of expression of the surface molecules (CD80, CD86 and MHC class I) and the production of the proinflammatory cytokines (IL-12 p70 and TNF-alpha) by LPS stimulation. Under our experimental conditions, curcumin plays an immunomodulatory role by downregulating IDO expression via a COX-2/PGE2-dependant pathway, thus impacting DC maturation in vitro and in vivo.

 

Edited by gamesguru, 28 August 2016 - 05:43 PM.