4029 replies to this topic

[lostfalco]

Seriously, lostfalco, it appears that your cognitive abstraction level has ascended several notches, inasmuch as I understand your point about having the best software in addition to the best hardware. But what's more atypical with regards to your posts above is their tenuous relevance to the topic of your own thread here. Granted, while I disagree with whoever labelled them as pointless and timewasting, it seems to me that perceiving such distant connections might equally be associated with enhanced mental function, as schizophrenia.

To cut to the chase, are you OK? I second raimis100 in inquiring as to any connection with BF-7, or some other recent change.

haha It's totally cool if someone (or 'someones') wants to vote all of those posts as time wasting...they're entitled to their opinion.

 

My opinion is that those posts are actually MORE important than any of my posts on supplements. No worries if someone disagrees. =)

 

To reveratrol_guy: Hey man...so your statement about my cognitive abstraction level assumes this: something about LF has changed. 

Then, you propose a few hypotheses to explain the 'change': 1. enhanced mental function, 2. schizophrenia, 3. BF-7, 4. some other recent change, etc.

 

The important thing here is to examine the first claim because if the claim that 'something has changed' is NOT true then there is no need to explain it. =)

 

Have I posted about similar topics in the past? Have the posts been of a similar type? (this isn't perfect, but it's good enough for our purposes)

Aug 2013: mention Kanhemann/Taversky, Robert Trivers, the cognitive psychology literature http://www.longecity...-14#entry602727

 

Aug 2013 I discuss individually necessary and jointly sufficient conditions. http://forum.bulletp...ge-3#entry40296

 

July 2013 I discuss optimizing my spacetime, Covey's countdown, change blindness, justification for enhancing healthy people, etc. http://forum.bulletp...nza/#entry35629   (ALL of these can be found on the Longecity thread as well...they're just all centralized at this link)

 

Oct 2013 I mention Yudkowsky, lesswrong.com, necessary and sufficient conditions, Baye's Theorem, biases/heuristics literature, etc.    http://www.longecity...46#entry619616 

 

Alright, that should be enough for now. That's everything the voices in my head told me to write about. =)

Edited by lostfalco, 30 October 2015 - 07:41 PM.

[lostfalco]

lostfalco has passed the point of no return. There's no hope for him anymore. If you follow his path... you'll end up like him.

haha There is no coming back from the depths to which I have descended. Let my tragic example be an object lesson to all about the follies of tinkering with one's mind!

Edited by lostfalco, 30 October 2015 - 08:30 PM.

[lostfalco]

A few posts about heuristic thinking/techniques and one gets labeled as schizophrenic? Going through the 86 pages of this thread, one would see that Falco has posted a lot of studies, articles, and presentations about models of thinking, neuroscientific research in regards to sensory substitution, and I believe even some math/physics related stuff (he's at least sent me some math/physics related ideas in the past). 

Thanks, Papa! Didn't you and I just post about the origins of life a few weeks ago? http://www.longecity...-85#entry746499

 

Speaking of physics...I have def talked a lot about it in the past. Here are links to Chiasson's work on Cosmic Evolution, Einstein's work on photoelectrons, Hoffman's (a physicist turned biologist) discussion of biology...again, posted in 2013.   http://www.longecity...1887-lostfalco/

Edited by lostfalco, 30 October 2015 - 06:15 PM.

[lostfalco]

But what's more atypical with regards to your posts above is their tenuous relevance to the topic of your own thread here. 

To cut to the chase, are you OK? 

I'll just comment on your post one more time, and then I'll stop (I genuinely hope it doesn't seem like I'm picking on you...that is not my intent!). 

 

First, I really do appreciate your concern for my well-being. I'm actually doing great. =)

 

Regarding the relevance of my recent posts...In my opinion, they are directly connected to the main topic of the the thread. 

1. What is the prior probability that any supplement I take is going to work? Have I neglected to consider the base rate when thinking about these topics?

2. We are doing experiments on ourselves (humans). What is a human? What is a human mostly made of? What do our senses tell us about what it means to be human? Are our senses reliable? Given the primary 'stuff' a human is made of, what does this tell us about where to look for possible enhancements? 

3. Do we have experimental confirmation of Galileo's theory? What does this tell us about assumptions we make when looking at the world, reading journal articles, experimenting on ourselves, etc.? (I think it's very likely that I would have thought they fell at different rates if I had not been taught about air resistance in elementary school) Are there things which seem obvious to me (hammer and feather fall at different rates) that are disconfirmed by theory/experiment?

4. The Monty Hall problem reveals one of the most pervasive statistical biases/illusions in human thinking...does this bias affect me when I am reading 'statistical' analyses in journal articles? Are there any other statistical illusions that I bring to the table when I read articles, view the world, experiment on myself, etc.? Are there new ways of thinking/reframing problems that might help me find new solutions when I'm experimenting on myself? Are there ways I can simplify problems to make them more understandable/solvable?

 

Tbh, those actually seem pretty relevant to me. =)

 

Ok, that should just about cover it.

Edited by lostfalco, 30 October 2015 - 08:33 PM.

[Groundhog Day]

Any of you guys doing LT have issues with the LED board coming apart?

 

I bought this one: http://www.amazon.co...ailpage_o07_s00

 

And I removed the glass as per Lostfalco's recommendation and the LED board soon popped loose so I have keep my hand on the board to use it.

 

Should I return it or are they all like this? (at this price range)

[abelard lindsay]

Lots of great info on this thread!  However,  it's important to be careful with odd stacks and such with things like bf-7.  I have propelled myself into undesirable  states temporarily  while exploring certain neurochemical pathways with stacks, and thus, due to recent concerns, a note on amphetamine psychosis is in order:

 

A good way to find out if one could possibly be experiencing amphetamine psychosis, IMHO, is to watch the great Phillip K. Dick movie " A Scanner Darkly".  If one finds oneself acting and talking like some of the junkies in that movie it's a good indication that one needs to lay off the dopaminerics for a while and learn to talk oneself out of any thoughts that are likely eminating from that state of mind.  Check with your doctor, of course, if you suspect you are suffering from a serious mental health condition.

 

This is why I avoid direct dopamine agonists or anything that heavily influences dopamine presence in the synaptic cleft.  Not worth it.

Edited by abelard lindsay, 31 October 2015 - 02:55 AM.

[resveratrol_guy]

Hey lostfalco, I'm glad to hear you're OK and behaving in what you have demonstrated is a statistically typical state with respect to your posts. BigPapaChaka said I labelled you a schizophrenic. I didn't, not that I actually think it's somehow a deragatory term, for that matter.

 

Anyway I thank you for your thorough answer. These things matter when we're dumping all sorts of new substances into our brains in the hope of eliciting some improvement.

[lostfalco]

Hey lostfalco, I'm glad to hear you're OK and behaving in what you have demonstrated is a statistically typical state with respect to your posts. BigPapaChaka said I labelled you a schizophrenic. I didn't, not that I actually think it's somehow a deragatory term, for that matter.

 

Anyway I thank you for your thorough answer. These things matter when we're dumping all sorts of new substances into our brains in the hope of eliciting some improvement.

Hey resveratrol_guy, no worries at all! I really hope you didn't take my posts as attacks in any way. I know you were just concerned about what you saw as a change and were making guesses about the possible cause or causes. I have no doubt you weren't the only one thinking it anyway. Don't worry, I've always been this weird/abstract. ha 

 

I 100% agree with you that schizophrenic is not a derogatory term...in fact, I'm pretty much certain that BigPapa didn't mean it that way either. He's been very open about his own struggles with HPPD and is accutely aware of how difficult mental health challenges can be.

 

No problem about the answers. I hope they connect the posts about rationality/biases a little better to the posts on journal articles/supplements. =) 

 

I think you're totally right that dumping combinations of risky/unknown substances into our brains requires some serious thought. For example, I dropped galantamine (which raises acetylcholine levels) before starting BF-7 (which may also raise acetylcholine...although the mechanism/s for BF-7 are not clear at all). Never hurts to attempt to minimize risks as much as possible. The good thing about BF-7 is that it is a peptide (mostly just glycine, alanine, and serine) and has been ingested for thousands of years. I think our risk here is on the low side but it's definitely non-zero. 

 

Anyway, thanks for checking out the thread and I hope you'll keep hanging around and posting! It never hurts to question things/people. That's how we grow, after all. 

Edited by lostfalco, 31 October 2015 - 05:25 AM.

[resveratrol_guy]

 

Hey lostfalco, I'm glad to hear you're OK and behaving in what you have demonstrated is a statistically typical state with respect to your posts. BigPapaChaka said I labelled you a schizophrenic. I didn't, not that I actually think it's somehow a deragatory term, for that matter.

 

Anyway I thank you for your thorough answer. These things matter when we're dumping all sorts of new substances into our brains in the hope of eliciting some improvement.

Hey resveratrol_guy, no worries at all! I really hope you didn't take my posts as attacks in any way. I know you were just concerned about what you saw as a change and were making guesses about the possible cause or causes. I have no doubt you weren't the only one thinking it anyway. Don't worry, I've always been this weird/abstract. ha 

 

I 100% agree with you that schizophrenic is not a derogatory term...in fact, I'm pretty much certain that BigPapa didn't mean it that way either. He's been very open about his own struggles with HPPD and is accutely aware of how difficult mental health challenges can be.

 

No problem about the answers. I hope they connect the posts about rationality/biases a little better to the posts on journal articles/supplements. =) 

 

I think you're totally right that dumping combinations of risky/unknown substances into our brains requires some serious thought. For example, I dropped galantamine (which raises acetylcholine levels) before starting BF-7 (which may also raise acetylcholine...although the mechanism/s for BF-7 are not clear at all). Never hurts to attempt to minimize risks as much as possible. The good thing about BF-7 is that it is a peptide (mostly just glycine, alanine, and serine) and has been ingested for thousands of years. I think our risk here is on the low side but it's definitely non-zero. 

 

Anyway, thanks for checking out the thread and I hope you'll keep hanging around and posting! It never hurts to question things/people. That's how we grow, after all. 

 

 

Yes, I was genuinely concerned about your mental status. Your experiments have been of outstanding value to us all, and I think we all realize that such endeavors are not without their risks. I'm convinced by your citations that you are behaving normally!

 

But do tell... why did you dump galantamine -- just because you didn't want to overstimulate acetylcholine? This was next on my list because it supposedly clears amyloid precursor protein from the cerebrovasculature (can't find the study at the moment).

 

 

[lostfalco]

Lots of great info on this thread!  However,  it's important to be careful with odd stacks and such with things like bf-7.  I have propelled myself into undesirable  states temporarily  while exploring certain neurochemical pathways with stacks, and thus, due to recent concerns, a note on amphetamine psychosis is in order:

 

A good way to find out if one could possibly be experiencing amphetamine psychosis, IMHO, is to watch the great Phillip K. Dick movie " A Scanner Darkly".  If one finds oneself acting and talking like some of the junkies in that movie it's a good indication that one needs to lay off the dopaminerics for a while and learn to talk oneself out of any thoughts that are likely eminating from that state of mind.  Check with your doctor, of course, if you suspect you are suffering from a serious mental health condition.

 

This is why I avoid direct dopamine agonists or anything that heavily influences dopamine presence in the synaptic cleft.  Not worth it.

Thanks, Abelard!

 

I totally agree about being careful. It's much easier to hurt yourself than help yourself.

[lostfalco]

Any of you guys doing LT have issues with the LED board coming apart?

 

I bought this one: http://www.amazon.co...ailpage_o07_s00

 

And I removed the glass as per Lostfalco's recommendation and the LED board soon popped loose so I have keep my hand on the board to use it.

 

Should I return it or are they all like this? (at this price range)

Hey Groundhog, I've had this issue too. They are pretty much all like this. I recommend pressing the LEDs into your skin in order to enhance penetration of the light and this usually holds it in place for me. See this video for the reason behind pressing down. 

 

[lostfalco]

 

Yes, I was genuinely concerned about your mental status. Your experiments have been of outstanding value to us all, and I think we all realize that such endeavors are not without their risks. I'm convinced by your citations that you are behaving normally!

 

But do tell... why did you dump galantamine -- just because you didn't want to overstimulate acetylcholine? This was next on my list because it supposedly clears amyloid precursor protein from the cerebrovasculature (can't find the study at the moment).

 

Thanks, man!

 

I dropped galantamine while on BF-7 since I've never tried BF-7 before and don't know how it will affect me. I def recommend a galantamine experiment though. Try it out and let us know how it goes for you. 

[Logic]

I've been looking back over the research on the inner mitochondrial membrane (phosphatidylethanolamine, phosphatidylcholine, cardiolipin, etc.). It's still all over the place. DHA will look good in study A and then study B will show that it's detrimental. Such is the nature of science. ha

 

Possibly because DHA downregulates FOXO Lostfalco.
http://www.longecity...s-on-foxo-gene/

 

EPA not DHA for cognitive function?

http://www.longecity...itive-function/

 

DHA-Accelerated Aging Hypothesis

http://www.longecity...ing-hypothesis/

Edited by Logic, 04 November 2015 - 12:48 PM.

[lostfalco]

Rodent study. As most of you know, I like using PDE5i (tadalafil or sildenafil, primarily) for cyclic GMP enhancement...very speculative on my part but worth a try imo. =)

 

This study uses PDE2i...different, but similar. 

 

http://www.ncbi.nlm....pubmed/26525565

 

Psychopharmacology (Berl). 2015 Nov 2. [Epub ahead of print]

Cyclic GMP-mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice.

Lueptow LM1,2, Zhan CG3, O'Donnell JM4.

Author information

Abstract

RATIONALE AND OBJECTIVES: 

Cyclic nucleotide phosphodiesterase-2 (PDE2) is a potential therapeutic target for the treatment of cognitive dysfunction. Using the object recognition test (ORT), this study assessed the effects of two PDE2 inhibitors, Bay 60-7550 and ND7001, on learningand memory, and examined underlying mechanisms.

METHODS: 

To assess the role of PDE2 inhibition on phases of memory, Bay 60-7550 (3 mg/kg) was administered: 30 min prior to training; 0, 1, or 3 h after training; or 30 min prior to recall testing. To assess cyclic nucleotide involvement in PDE2 inhibitor-enhanced memory consolidation, either the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg; intraperitoneal (IP)), soluble guanylyl cyclase inhibitor 1H-[-1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 20 mg/kg; IP), protein kinase G inhibitor KT5823 (2.5 μg; intracerebroventricular (ICV)), or protein kinase A inhibitor H89 (1 μg; ICV) was administered 30 min prior to the PDE2 inhibitor Bay 60-7550 (3 mg/kg) or ND7001 (3 mg/kg). Changes in the phosphorylation of 3'5'-cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) at Ser-133 and vasodilator-stimulated phosphoprotein (VASP) at Ser-239 were determined to confirm activation of cAMP and 3'5'-cyclic guanosine monophosphate (cGMP) signaling.

RESULTS: 

Bay 60-7550 (3 mg/kg) enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg) on early consolidation processes. Bay 60-7550 (3 mg/kg) enhanced phosphorylation of CREB and VASP, both targets of cGMP-dependent protein kinase (PKG).

CONCLUSIONS: 

These results confirm a potential of PDE2, or components of its signaling pathway, as a therapeutic target for drug discovery focused on restoring memory function.

 

Edited by lostfalco, 04 November 2015 - 11:24 PM.

[lostfalco]

 

I've been looking back over the research on the inner mitochondrial membrane (phosphatidylethanolamine, phosphatidylcholine, cardiolipin, etc.). It's still all over the place. DHA will look good in study A and then study B will show that it's detrimental. Such is the nature of science. ha

 

Possibly because DHA downregulates FOXO Lostfalco.
http://www.longecity...s-on-foxo-gene/

 

EPA not DHA for cognitive function?

http://www.longecity...itive-function/

 

DHA-Accelerated Aging Hypothesis

http://www.longecity...ing-hypothesis/

 

Thanks for the links, Logic!

 

Those are possibilities, but then you get studies like this. "DHA stimulates a mechanism to self-protect from oxidative damage..."

 

I'm still trying to figure out where I stand on the issue. 

 

http://www.ncbi.nlm....pubmed/26257655

 

Front Physiol. 2015 Jul 22;6:203. doi: 10.3389/fphys.2015.00203. eCollection 2015.

Docosahexaenoic (DHA) modulates phospholipid-hydroperoxide glutathione peroxidase (Gpx4) gene expression to ensure self-protection from oxidative damage in hippocampal cells.

Casañas-Sánchez V1, Pérez JA1, Fabelo N2, Quinto-Alemany D2, Díaz ML2.

Author information

Abstract

Docosahexaenoic acid (DHA, 22:6n-3) is a unique polyunsaturated fatty acid particularly abundant in nerve cell membrane phospholipids. DHA is a pleiotropic molecule that, not only modulates the physicochemical properties and architecture of neuronal plasma membrane, but it is also involved in multiple facets of neuronal biology, from regulation of synaptic function to neuroprotection and modulation of gene expression. As a highly unsaturated fatty acid due to the presence of six double bonds, DHA is susceptible for oxidation, especially in the highly pro-oxidant environment of brain parenchyma. We have recently reported the ability of DHA to regulate the transcriptional program controlling neuronal antioxidant defenses in a hippocampal cell line, especially the glutathione/glutaredoxin system. Within this antioxidant system, DHA was particularly efficient in triggering the upregulation of Gpx4 gene, which encodes for the nuclear, cytosolic, and mitochondrial isoforms of phospholipid-hydroperoxide glutathione peroxidase (PH-GPx/GPx4), the main enzyme protecting cell membranes against lipid peroxidation and capable to reduce oxidized phospholipids in situ. We show here that this novel property of DHA is also significant in the hippocampus of wild-type mice and, to a lesser extent in APP/PS1 transgenic mice, a familial model of Alzheimer's disease. By doing this, DHA stimulates a mechanism to self-protect from oxidative damage even in the neuronal scenario of high aerobic metabolism and in the presence of elevated levels of transition metals, which inevitably favor the generation of reactive oxygen species. Noticeably, DHA also upregulated a Gpx4 CIRT (Cytoplasmic Intron-sequence Retaining Transcripts), a novel Gpx4 splicing variant, harboring part of the first intronic region, which according to the "sentinel RNA hypothesis" would expand the ability of Gpx4 (and DHA) to provide neuronal antioxidant defense independently of conventional nuclear splicing in cellular compartments, like dendritic zones, located away from nuclear compartment. We discuss here, the crucial role of this novel transcriptional regulation triggered by DHA in the context of normal and pathological hippocampal cell.

 

 

Edited by lostfalco, 04 November 2015 - 11:46 PM.

[lostfalco]

Speaking of sildenafil...

 

http://www.sciencedi...014488615301138

 

 

Phosphodiesterase-5 inhibition promotes remyelination by MCP-1/CCR-2 and MMP-9 regulation in a cuprizone-induced demyelination model

 

Highlights

 

•Sildenafil (Viagra®, Pfizer) protects CNS and the mechanisms still unknown.
•Herein, the mechanism of protection was examined in cuprizone-demyelinatingmodel.
•It was showed that sildenafil protects myelin and increases MCP-1/CCR-2 and MMP-9.
•This mechanism can contribute to balance inflammation.
•The protection was more effective starting early and for longer.

 

Abstract

While it has recently been shown that sildenafil (Viagra®) has a protective effect on myelination/remyelination, the mechanism of this protection is still unknown. In general, cytokines, chemokines and metalloproteinases have a pro-inflammatory action, but can also exert a role in modulating glial cell activation, contributing to the balance of cell response. Investigating these molecules can contribute to clarifying the mechanisms of sildenafil neuroprotection. In addition, it is not known whether sildenafil is able to restore an already installed neurodegenerative process or if the treatment period is critical for its action. The aim of the present study was to evaluate, in a cuprizone (CPZ)-induced demyelination model, the effects and mechanisms of time-dependent treatment with sildenafil (beginning 15 days after neurodegeneration and continuing for 15 days, or starting concomitantly with neurodegeneration and continuing for 30 days) on neuroinflammation and remyelination. Neuroinflammation and demyelination induced by CPZ in rodents has been widely used as a model of multiple sclerosis (MS). In the present study, five male C57BL/6 mice aged 7–10 weeks were used per group. For four weeks, the groups received either cuprizone (CPZ) 0.2% mixed in feed or CPZ combined with the administration of sildenafil (Viagra®, Pfizer, 25 mg/kg) orally in drinking water, starting concurrently with (sild-T0) or 15 days (sild-T15) after the start of CPZ treatment. Control animals received pure food and water. The cerebella were dissected and processed for immunohistochemistry, immunofluorescence (frozen), Western blotting, luxol fast blue staining and transmission electron microscopy. Magnetic resonance was performed for live animals, after the same treatment, using CPZ 0.3%. CPZ induced an increase in the expression of IL-1β and a decrease in MCP-1, CCR-2, MBP and GST-pi, as well as promoting damage in the structure and ultra-structure of the myelin sheath. Interestingly, the administering of sild-T0 promoted a further increase of MMP-9, MCP-1, and CCR-2, possibly contributing to changes in the microglia phenotype, which become more phagocytic, cleaning myelin debris. It was also observed that, after sild-T0 treatment, the expression of GST-pi and MBP increased and myelin structure was improved. However, sild-T15 was not efficient in all aspects, probably due to the short treatment period and to starting after the installation of the degenerative process. Therefore, the present study shows that sildenafil modulates inflammation, with the involvement of MMP-9, MCP-1, and CCR-2, and also contributes to myelin repair. These protective effects were dependent on the therapeutic strategy used. This clarification can strengthen research proposals into the mechanism of action of sildenafil and contribute to the control of neurodegenerative diseases such as MS.

 

Edited by lostfalco, 05 November 2015 - 12:15 AM.

[lostfalco]

A lot of interesting research on PDE5i right now. Rodent study, disease model.

 

"Normalization of NMDA and AMPA receptors by sildenafil treatment would contribute to restore signal transduction and learning ability."

 

"Sildenafil normalizes IL-1β levels in hippocampus, membrane expression of all receptors and spatial learning in the radial and Morris water mazes."

 

"The mechanisms by which sildenafil reduces neuroinflammation would involve cGMP increase and activation of cGMP-dependent protein kinase (PKG)."

 

"Treatment with sildenafil normalizes IL-1β levels, phosphorylation of p38 and membrane expression of GABAA, AMPA, and NMDA receptors and restores spatial learning ability."

 

http://www.ncbi.nlm....les/PMC4625867/

 

J Neuroinflammation. 2015 Oct 29;12(1):195. doi: 10.1186/s12974-015-0420-7.

Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms.

Hernandez-Rabaza V1, Agusti A2, Cabrera-Pastor A1, Fustero S3,4, Delgado O3,4, Taoro-Gonzalez L1, Montoliu C2, Llansola M1, Felipo V5.

Author information

Abstract

BACKGROUND: 

There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and © analyze the underlying mechanisms.

METHODS: 

Neuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GABA and glutamate receptors was analyzed using BS3 cross-linker. Spatial learning was analyzed using the radial and Morris water mazes. To assess if sildenafil reverses the alterations, rats were treated with sildenafil in the drinking water.

RESULTS: 

PCS rats show increased IL-1β and TNF-α levels and phosphorylation (activity) of p38 in hippocampus. Membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA receptor are increased in PCS rats, while subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors are reduced. PCS rats show reduced spatial learning in the radial and Morris water mazes. Sildenafil treatment normalizes IL-1β and TNF-α levels, p38 phosphorylation, and membrane expression of GABAA, AMPA, and NMDA receptors and restores spatial learning.

CONCLUSIONS: 

Increased IL-1β alters GABAergic and glutamatergic neurotransmission in hippocampus and impairs spatial learning in rats with MHE. Sildenafil reduces neuroinflammation and restores learning. Phosphodiesterase-5 inhibitors may be useful to improve cognitive function in patients with MHE.

 

Edited by lostfalco, 05 November 2015 - 12:54 AM.

[Logic]

Thanks for the links, Logic!

 

 

Those are possibilities, but then you get studies like this. "DHA stimulates a mechanism to self-protect from oxidative damage..."

 

I'm still trying to figure out where I stand on the issue. 

 

Pleasure  

I think its a case of getting the ratio just right with more DHA required during the growth of the brain.
There's info on that somewhere in those links.

For PDE-5 inhibition check out Horney goat weed/Icariin etc:
http://www.longecity...natural-pharma/

HGW has a good # of other... 'fun effects' too!

 

[BigPapaChakra]

I'll post a small excerpt of an article that someone (highly intelligent, researched, etc.) I know is currently writing regarding the biophysical/physical chemistry around DHA and other lipids, but he prefaces the article (I've only got an excerpt myself, but the excerpt I have is still many pages long) with some general information regarding how much DHA seems to even be needed during periods of massive brain growth, let alone in someone in good health:

 

"DHA is Important, but how much do Humans need?

How much DHA is there in breast milk? – http://ajcn.nutritio.../85/6/1457.full

The best estimates of worldwide mean breast-milk DHA and AA concentrations (wt:wt) from the primary analysis group are 0.32 ± 0.22% for DHA and 0.47 ± 0.13% for AA

That’s a high of 0.55% DHA as a percentage of all fatty acid content of breast milk.

How much breast milk do infants drink per day? – http://ajcn.nutritio.../59/3/600.short

In infants exclusively breast-fed, mean milk intake was 781 and 855 mL/24 h at 2 and 4 mo, respectively, and correlated positively with the current weight of the infant and negatively with the amount of formula supplement given at the maternity ward

How much fat is there in breast milk? ‘Macronutrient, mineral and trace element composition of breast milk from Japanese women’(Namiko Yamawaki et. al., 2005) – http://www.sciencedi...946672X05001008

lipids, 3.46±1.49 g/100 mL

This is from Japanese women, who generally have higher DHA concentrations in their breast milk.

So let’s assume that 1,000mL of breast milk is consumed per day (over-estimate), and let’s assume the high end of the fatty acid concentration of 3.46 + 1.49 = 4.95g/100mL breast milk.

Total Infant MAX Daily DHA Consumption = 4.95 * 10 * 0.0055 = 0.272g = 272.2mg
Average DHA Consumption = 3.46 * 8.55 * 0.0032 = 99.8mg

This is when you are trying you darnest best to build a human brain, and that you need is 100-272mg of DHA. For context, 100g of sardines typically would deliver 500mg of DHA."

 

(...) 

 

"How much brain DHA is recycled on a daily basis? ‘Docosahexaenoic Acid (DHA): An Ancient Nutrient for the Modern Human Brain ‘(Joanne Bradbury, 2011) – http://www.ncbi.nlm....les/PMC3257695/

Sidenote: There are 2 similar studies which I won’t go into here, but they basically got similar results:

• ‘Dietary intake and status of n−3 polyunsaturated fatty acids in a population of fish-eating and non-fish-eating meat-eaters, vegetarians, and vegans and the precursor-product ratio of α-linolenic acid to long-chain n−3 polyunsaturated fatty acids: results from the EPIC-Norfolk cohort’ (Welch et. al., 2010) –http://ajcn.nutritio.../92/5/1040.full

• ‘Long-chain n–3 polyunsaturated fatty acids in plasma in British meat-eating, vegetarian, and vegan men’(Rosell et. al., 2005) – http://ajcn.nutritio...t/82/2/327.full

This paper by Bradbury claims that brain DHA flux is about 3.8 ± 1.7 mg/day, with an estimated daily incorporation rate of 0.076% per day, and a 2.5 year half-life for DHA in the brain. See section 5 for the methodology used to determine this number."

[BigPapaChakra]

Here's another portion:

 

"

Total Retina DHA Flux Unknown

First off, you’ll see places which state that “DHA is 60% of the Retina’s lipis”.

I honestly couldn’t find a study which supported that claim:

• ‘Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants.’ (Makrides et. al., 1994) –http://www.ncbi.nlm..../pubmed/7913291

  Infant study, so I’d expect a lower DHA concentration. DHA is 12.3 +- 2.1% of total fatty acids by weight in the High DHA diet.

• ‘Fatty acid composition of the human macula and peripheral retina.’ (F J van Kuijk and P Buck, 1992) – http://iovs.arvojour...ticleid=2178624

  DHA 15.9% of total fatty acids in macular, 22.3% in the peripheral retina.

• ‘Lipids of human retina, retinal pigment epithelium, and Bruch’s membrane/choroid: comparison of macular and peripheral regions.’ (Gülcan et. al., 1993) – http://iovs.arvojour...ticleid=2160942

  • In Phospholipids: DHA consists 8.4 +- 2.1% total lipids in the macular, 9.4 +- 2.0% in the periphery
  • In Neutral Lipids: DHA consists 3.3 +- 2.5% total lipids in the macular, 2.6 +- 0.9% in the periphery

  There are about 5 times as much Neutral Lipids compared to Phospholipids in the retina (Figure 3 in paper), so the total amount of DHA is more akin to (8.4 + 9.4) * ¹⁄₆ + (3.3 + 2.6) * ⁵⁄₆ = 7.883% on average.

  The DHA content of the Retinal Pigment Epithelium and Bruch’s Membrane / Choroid are very low, less than 1% of total fatty acids in either of the Macula or Periphery.

In any case, it’s not as high as purported, though 20+% of total lipids is still a lot.

Much more important questions are:

• How much DHA does the entire eye contain (in terms of weight)?
• How much DHA gets recyled on a daily basis (in terms of weight)?
• Where is the DHA in the eye located? (hinting at what it is functionally doing)

We need to know answers to these questions, and the factors which influence the answers, to be able to say if endogenous DHA synthesis rates can meet retinal DHA demands (and therefore actually support the need for lower DHA intake), and to actually define DHA demands.

I do not dispute that DHA is important for the eye in general. But there are 2 concerns that I have with existing studies:

• (again) PUFA intake is often kept high. What if tests involved low PUFAs from any form? Will this still lead to retinal (or brain) DHA deficiency?

  NOTE: Because there is basically no PUFA in the retina to begin with, the “n-3 displacement of n-6 fatty acids” factor does not come into play in the retina. Here we are mostly talking about systemic inflammatory effects of PUFA.

  Most populations have high levels of PUFAs in their tissues (with the exception of maybe some of the Japanese). But what of the case whereby low tissue PUFA content has been attained? Should extra DHA be added in this case?

In any case, this is not a straightforward answer. DHA is actually not helpful in many tissues. That’s the topic of the next section …."

[BigPapaChakra]

What's really interesting is you have all this data, yet some of the same researchers give presentations on the Aquatic Ape Hypothesis and crap like that and aquatic based diets leading to our brain encephalization, with dietary estimates of n3 PUFA being well over 20g/day, sometimes much higher, and with just as much or more n6 PUFA; this contradicts their own published data, and goes against other published data in humans showing, in the very best scenario, a biphasic dose response curve (with DHA), where benefits start to drop off after about 230 mg/day. One interesting reason to have DHA enriched membranes is:

 

http://www.ncbi.nlm..../pubmed/9807808

 

Cholesterol versus cholesterol sulfate: effects on properties of phospholipid bilayers containing docosahexaenoic acid.

 

The important omega-3 fatty acid docosahexaenoic acid (DHA) is present at high concentration in some membranes that also contain the unusual sterol cholesterol sulfate (CS). The association between these lipids and their effect on membrane structure is presented here. Differential scanning calorimetry (DSC), MC540 fluorescence, erythritol permeability, pressure/area isotherms on lipid monolayers and molecular modeling are used to compare the effect of CS and cholesterol on model phospholipid membranes. By DSC, CS decreases the main phase transition temperature and broadens the transitions of dipalmitolyphosphatidylcholine (DPPC), 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (18:0,18:1 PC) and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (18:0,22:6 PC) to a much larger extent than does cholesterol. In addition CS produces a three-component transition in 18:0,18:1 PC bilayers that is not seen with cholesterol. In a mixed phospholipid bilayer composed of 18:0,18:1 PC/18:0,22:6 PC (1:1, mol/mol), CS at 2.5 membrane mol% or more induces lateral phase separation while cholesterol does not. CS decreases lipid packing density and increases permeability of 18:0,18:1 PC and 18:0,22:6 PC bilayers to a much larger extent than cholesterol. CS disrupts oleic acid-containing bilayers more than those containing DHA. Molecular modeling confirms that the anionic sulfate moiety on CS renders this sterol more polar than cholesterol with the consequence that CS likely resides higher (extends further into the aqueous environment) in the bilayer. CS can therefore be preferentially accommodated into DHA-enriched bilayers where its tetracyclic ring system may fit into the delta 4 pocket of DHA, a location excluded to cholesterol. It is proposed that CS may in part replace the membrane function of cholesterol in DHA-rich membranes.

 

This doesn't require DHA supplements, though, nor an aquatic based diet that people such as Jack Kruse, Cunnane, etc. recommend. 

[lostfalco]

A few people have asked me about this recently so I figured I would share with everyone. There is an excellent issue of Neuropharmacology completely devoted to Cognitive Enhancers from back in 2013. The whole thing is available online for free here! http://www.sciencedi...nal/00283908/64

 

This issue discusses HDAC inhibitors, Ampakines, NMDARs, Pregnenolone Sulfate, Modafinil, D-Cycloserine, tDCS, glucose, noradrenaline enhancement, tadalafil/PDEi, caffeine, nicotine, dopamine, omega-3's, etc....just about every major theme of this thread. Check it out. It's an amazing read. Here are links to some of the free full text articles from the issue. 

 

The first article touches on so many critical issues I just have to link it. It's a thing of beauty. http://www.sciencedi...028390812003097

 

Tadalafil is one of my most recent experiments. This article discusses its ability to cross the blood brain barrier and enhance cognition in Alzheimer's models.  http://www.sciencedi...028390812003206

 

Neuroscientist Gary Lynch (who I've talked about a bit) has an excellent article on ampakines and LTP timing rules/thresholds. http://www.sciencedi...02839081200336X

 

The Picower Institute for Learning and Memory gang makes an appearance to discuss HDACi. http://www.sciencedi...028390812003012

 

The list goes on and on. Enjoy!

Edited by lostfalco, 06 November 2015 - 05:53 AM.

[lostfalco]

I've mentioned this before...but it's been a while. There is some evidence that tadalafil/sildenafil are HDAC2 inhibitors. Here's how it works: PDE5i increases NO, nitrosylates HDAC2, dissociates HDAC2 from chromatin, enhances learning and memory gene expression/BDNF, causes positive feedback loop for learning and memory. So badass!

 

Sorry about the extended quotes below! I just can't resist. Here's the free full text pdf on HDAC inhibitors, "Histone deacetylases in memory and cognition."   HDAC2.pdf   313.4KB   2 downloads

 

"Because BDNF is a well-established HDAC2 target gene, it is worth noting that BDNF and HDAC2 could form the core of a positive feedback loop in synaptic plasticity (Fig. 1) (3). That is, the activity-dependent secretion of BDNF in response to a synaptic plasticity–inducing stimulus would be expected, through NOS and NO, to promote HDAC2 dissociation from chromatin. This removal of HDAC2 inhibition would then promote the expression of plasticity-related transcripts, including BDNF, which would further stimulate synaptic plasticity and further inhibit HDAC2-mediated repression. Similarly, stimuli that inhibit HDAC2 activity could prime BDNF expression, ultimately further inhibiting HDAC2 activity. Although this type of positive feedback loop has not been experimentally tested in neurons, it is an attractive mechanism to coordinate chromatin acetylation modifications with neuronal activity to enact lasting changes in the transcriptional potential of plasticity-associated genes."

 

 

"In response to treatment with BDNF, NGF (nerve growth factor), or Ca2+ ionophore in rat cortical neurons, HDAC2 was rapidly nitrosylated on cysteines 262 and 274 in an nNOS- and NO-dependent manner (78). Nitrosylation did not affect the deacetylase activity of HDAC2 but rather inhibited its association with chromatin. Consistently, stimulation of PC12 cells with NGF, a plasticity-promoting neurotrophin, induced dissociation of HDAC2 from target gene promoters and enhanced histone acetylation at these same locations (78, 79). A non-nitrosylatable form of HDAC2 did not dissociate from target gene promoters upon NGF treatment and prevented the increase in acetylation at these sites normally induced by NGF. These findings indicate that nitrosylation can suppress the ability of HDAC2 to inhibit gene expression during cognitive function, and they also illustrate how HDAC residence at target gene promoters can antagonize histone acetylation activity."

 

http://www.ncbi.nlm....pubmed/25492968

 

Sci Signal. 2014 Dec 9;7(355):re12. doi: 10.1126/scisignal.aaa0069.

Histone deacetylases in memory and cognition.

Penney J1, Tsai LH2.

Author information

Abstract

Over the past 30 years, lysine acetylation of histone and nonhistone proteins has become established as a key modulator of gene expression regulating numerous aspects of cell biology. Neuronal growth and plasticity are no exception; roles for lysine acetylation and deacetylation in brain function and dysfunction continue to be uncovered. Transcriptional programs coupling synaptic activity to changes in gene expression are critical to the plasticity mechanisms underlying higher brain functions. These transcriptional programs can be modulated by changes in histone acetylation, andin many cases, transcription factors and histone-modifying enzymes are recruited together to plasticity-associated genes. Lysine acetylation, catalyzed by lysine acetyltransferases (KATs), generally promotes cognitive performance, whereas the opposing process, catalyzed by histone lysine deacetylases (HDACs), appears to negatively regulate cognition in multiple brain regions. Consistently, mutation or deregulation of different KATs or HDACs contributes to neurological dysfunction and neurodegeneration. HDAC inhibitors have shown promise as a treatment to combat the cognitive decline associated with aging and neurodegenerative disease, as well as to ameliorate the symptoms of depression and posttraumatic stress disorder, among others. In this review, we discuss the evidence for the roles of HDACs in cognitive function as well as in neurological disorders and disease. In particular, we focus on HDAC2, which plays a central role in coupling lysine acetylation to synaptic plasticity and mediates many of the effects of HDAC inhibition in cognition and disease.

 

 

http://www.ncbi.nlm....pubmed/24705918

 

Metab Brain Dis. 2014 Sep;29(3):673-82. doi: 10.1007/s11011-014-9533-4. Epub 2014 Apr 5.

Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice.

Wang C1, Zhang J, Lu Y, Lin P, Pan T, Zhao X, Liu A, Wang Q, Zhou W, Zhang HT.

Author information

Abstract

Inhibition of phosphodiesterase-4 or 5 (PDE4 or PDE5) increases cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP), respectively, which activates cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/neuropeptide VGF (non-acryonimic) signaling and produces antidepressant-like effects on behavior. However, causal links among these actions have not been established. In the present study, mice were evaluated for the effects of etazolate and sildenafil, the inhibitor of PDE4 or PDE5, respectively, on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in the forced-swimming test (FST) and tail suspension test (TST), in the presence or absence of the inhibitor of protein kinase A (PKA) or protein kinase G (PKG) via intracerebroventricular (i.c.v.) infusions. The levels of cAMP, cGMP and expression of pCREB, CREB, BDNF and VGF in both the hippocampus and prefrontal cortex were determined. The results showed that etazolate at 5.0 mg/kg or sildenafil at 30 mg/kg significantly reversed CUMS-induced depressive-like behavior; the effects were paralleled with the increased levels of cAMP/pCREB/BDNF/VGF or cGMP/pCREB/BDNF/VGF signaling, respectively. These effects were completely abolished following inhibition of PKA or PKG, respectively. The results suggest that inhibition of PDE4 by etazolate or PDE5 by sildenafil produced antidepressant-like effects in CUMS-treated animals via cAMP or cGMP signaling, which shares the common downstream signal pathway of CREB/BDNF/VGF.

 

Edited by lostfalco, 06 November 2015 - 07:08 AM.

[lostfalco]

A nice simple introduction to cGMP (which is enhanced by sildenafil/tadalafil). I recommend watching at 2x speed for most videos. =)

 

[lostfalco]

Another reminder of interesting experimental ideas relating to massive memory enhancement if anyone is interested in trying them out. =)

 

1. tadalafil/sildenafil + zembrin

2. tadalafil + zembrin + sodium butyrate

3. tadalafil +zembrin + sodium butyrate + resistant starch/fiber

4. tadalafil + zembrin + sodium butyrate + resistant starch/fiber + ALCAR

 

**obligatory serotonin warning here for zembrin. =) (if only I could find some rolipram...)

 

Reason: PDE5i enhances early LTP while PDE4i enhances late LTP in a synergistic fashion...AND PDE5i + HDACi has been shown to be synergistic as well. 

 

http://www.ncbi.nlm....les/PMC4207334/

 

Neuropsychopharmacology. 2014 Oct;39(11):2497-505. doi: 10.1038/npp.2014.106. Epub 2014 May 12.

Improved long-term memory via enhancing cGMP-PKG signaling requires cAMP-PKA signaling.

Bollen E1, Puzzo D2, Rutten K1, Privitera L2, De Vry J1, Vanmierlo T1, Kenis G1, Palmeri A2, D'Hooge R3, Balschun D3, Steinbusch HM1, Blokland A4, Prickaerts J1.

Author information

Abstract

Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation.

 

 

http://www.ncbi.nlm....pubmed/25896769

 

Neuropharmacology. 2015 Apr 17;95:361-366. doi: 10.1016/j.neuropharm.2015.04.008. [Epub ahead of print]

Object memory enhancement by combining sub-efficacious doses of specific phosphodiesterase inhibitors.

Bollen E1, Akkerman S1, Puzzo D2, Gulisano W2, Palmeri A2, D'Hooge R3, Balschun D3, Steinbusch HW1, Blokland A4, Prickaerts J5.

Author information

Abstract

The second messengers cGMP and cAMP have a vital role in synaptic plasticity and memory processes. As such, phosphodiesterases inhibitors (PDE-Is), which prevent the breakdown of these cyclic nucleotides, represent a potential treatment strategy in memory decline. Recently it has been demonstrated that cGMP and cAMP signaling act in sequence during memory consolidation, with early cGMP signaling requiring subsequent cAMP signaling. Here, we sought to confirm this relationship, and to evaluate its therapeutic implications. Combining sub-efficacious doses of the cGMP-specific PDE type 5 inhibitor vardenafil (0.1 mg/kg) and cAMP-specific PDE type 4 inhibitor rolipram (0.01 mg/kg) during the early and late memoryconsolidation phase, respectively, led to improved memory performance in a 24 h interval object recognition task. Similarly, such a sub-efficacious combination treatment enhanced the transition of early-phase long-term potentiation (LTP) to late-phase LTP in hippocampal slices. In addition, both object memory and LTP were improved after administration of two sub-efficacious doses of the dual substrate PDE type 2 inhibitor BAY60 7550 (0.3 mg/kg) at the early and late consolidation phase, respectively. Taken together, combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is have an additive effect on long-term synaptic plasticity and memory formation and might prove a superior alternative to single PDE-I treatment.

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

 

http://www.ncbi.nlm....pubmed/26457123

 

Clin Epigenetics. 2015 Oct 8;7:108. doi: 10.1186/s13148-015-0142-9. eCollection 2015.

Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease.

Cuadrado-Tejedor M1, Garcia-Barroso C2, Sanzhez-Arias J3, Mederos S4, Rabal O3, Ugarte A3, Franco R5, Pascual-Lucas M2, Segura V6, Perea G4, Oyarzabal J3, Garcia-Osta A2.

Author information

Abstract

BACKGROUND: 

Given the implication of histone acetylation in memory processes, histone deacetylase inhibitors (HDACIs) have been postulated as potential modulators of cognitive impairment in Alzheimer's disease (AD). However, dose-dependent side effects have been described in patients with the currently available broad-spectrum HDACIs, explaining why their therapeutic potential has not been realized for chronic diseases. Here, by simultaneously targeting two independent enzyme activities, histone deacetylase (HDAC) and phosphodiesterase-5 (PDE5), we propose a novel mode of inhibitory action that might increase the therapeutic specificity of HDACIs.

RESULTS: 

The combination of vorinostat, a pan-HDACI, and tadalafil, a PDE5 inhibitor, rescued the long-term potentiation impaired in slices from APP/PS1 mice. When administered in vivo, the combination of these drugs alleviated the cognitive deficits in AD mice, as well as the amyloid and tau pathology, and it reversed the reduced dendritic spine density on hippocampal neurons. Significantly, the combination of vorinostat and tadalafil was more effective than each drug alone, both against the symptoms and in terms of disease modification, and importantly, these effects persisted after a 4-week washout period.

CONCLUSIONS: 

The results highlight the pharmacological potential of a combination of molecules that inhibit HDAC and PDE5 as a therapeutic approach for AD treatment.

 

Edited by lostfalco, 07 November 2015 - 06:52 AM.

[Baten]

I've been taking tadalafil at ~10-15mg doses very often these past months. I've observed no memory enhancement benefits, honestly.

[lostfalco]

I've been taking tadalafil at ~10-15mg doses very often these past months. I've observed no memory enhancement benefits, honestly.

Hey Baten, thanks for reporting. Sorry it hasn't worked for you. It's a pretty complicated sequence from receptors to intracellular cascade to gene expression to memory enhancement. PDE5i only affects one step along the way. It looks like that step by itself isn't one that benefits your memory. Luckily, there are plenty of other things to try. =)

[magta39]

I have been taking 2 drops per day of superiorpeptide tadalafil for months, I feel it is the only thing so far that has really helped my memory, I also take it with 2 capsules argininge/citrulline because it seems synergistic.  Also this seems to work well with Noopept and piracetam.  Keep in mind I am 56 yrs old.  Also I am on BP meds which may affect my brain funcion.  I will add some sodium butyrate and see if helps. 

[StabMe]

Hey Falco!

Read the whole thread and have been lurking here for some time. Can you recommend the dosages of the aforementioned compounds?

Another reminder of interesting experimental ideas relating to massive memory enhancement if anyone is interested in trying them out. =)

1. tadalafil/sildenafil + zembrin
2. tadalafil + zembrin + sodium butyrate
3. tadalafil +zembrin + sodium butyrate + resistant starch/fiber
4. tadalafil + zembrin + sodium butyrate + resistant starch/fiber + ALCAR

[lostfalco]

I have been taking 2 drops per day of superiorpeptide tadalafil for months, I feel it is the only thing so far that has really helped my memory, I also take it with 2 capsules argininge/citrulline because it seems synergistic.  Also this seems to work well with Noopept and piracetam.  Keep in mind I am 56 yrs old.  Also I am on BP meds which may affect my brain funcion.  I will add some sodium butyrate and see if helps. 

Thanks for the report, magta. Tadalafil should def be synergistic with arginine/citrulline...and I love that you're keeping your dose low especially when combining with precursors!

 

At 56, I would guess that things like low dose selegiline (MAO-B) and/or galantamine (alpha 7 nicotinic receptor modulator, acetylcholinsterase inhibitor, kynurenic acid lowering, etc.) might be beneficial (though you would want to be careful with possible interactions with your BP meds). Have you tried these? My guess is that they would be more likely to help than sodium butyrate. 

 

Here's a rodent study hinting at synergistic effects between donepezil (which is somewhat similar to galantamine) and selegiline. Btw, I am NOT implying that you have Alzheimer's! ha 

 

http://www.ncbi.nlm....pubmed/18420288

 

Behav Brain Res. 2008 Jul 19;190(2):224-32. doi: 10.1016/j.bbr.2008.03.002. Epub 2008 Mar 18.

Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25-35).

Tsunekawa H1, Noda Y, Mouri A, Yoneda F, Nabeshima T.

Author information

Abstract

Selegiline, an irreversible inhibitor of monoamine oxidase B used in the treatment of Parkinson's disease, has been demonstrated to have a potential cognition-improving effect in patients with Alzheimer's disease (AD) undergoing treatment with an acetylcholinesterase inhibitor donepezil. To confirm such clinical events, we investigated whether co-administration of donepezil with selegiline had a synergistic cognition-improving effect in an animal model of AD. Intracerebroventricular injection of amyloid beta protein fragment 25-35 [Abeta(25-35)] induced impairment of learning and memory in a Y-maze, novel object recognition and contextual fear conditioning tests. Either donepezil or selegiline alone improved the cognitive impairments in the Y-maze and conditioned fear learning tasks in Abeta(25-35)-injected mice, whereas donepezil, but not selegiline, failed to improve the impairment in a novel object recognition task. Co-administration of donepezil with selegiline, at doses that do not exert efficacy individually, significantly improved the deficits in all three tests, indicating a synergistic cognition-improving effect. These alleviating effects were antagonized by pretreatment with a muscarinic receptor antagonist scopolamine and a dopamine receptor antagonist haloperidol. These results suggest that selegiline potentiates the effect of donepezil on the cognitive impairment, and that the synergistic effect may be mediated through both the cholinergic and dopaminergic systems.

Edited by lostfalco, 07 November 2015 - 05:57 PM.