4029 replies to this topic

[lostfalco]

Abelard my friend, are you out there? This one's for you!

 

Rodent Study:

non-emetic (projectile vomit) doses of roflumilast = enhanced memory

non-efficacious doses of roflumilast + donepezil = corrected memory deficits  

 

https://www.ncbi.nlm...pubmed/26794595

 

Behav Brain Res. 2016 Apr 15;303:26-33. doi: 10.1016/j.bbr.2016.01.031. Epub 2016 Jan 18.

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses.

Vanmierlo T1, Creemers P2, Akkerman S2, van Duinen M2, Sambeth A3, De Vry J2, Uz T4, Blokland A3, Prickaerts J5.

Author information

Abstract

Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

 

Edited by lostfalco, 25 March 2016 - 08:09 PM.

[lostfalco]

This is just beautiful! I used this combo for a bit (as part of The God Stack) and highly recommend it (along with intranasal insulin). 

 

Risk Level: high, but not ridiculously high

 

leucine (whey protein would almost certainly work) + pde5i (tadalafil, sildenafil, etc.) = increased insulin sensitivity and fat burning

 

Note the use of subtherapeutic doses! Remember the theory behind The God Stack: MANY small enhancements from numerous different angles adds up to more than the sum of the parts. 1 + 1 + 1 + 1 + 1 = 1,000

 

https://www.ncbi.nlm...pubmed/25999751

 

Diabetes Metab Syndr Obes. 2015 May 6;8:227-39. doi: 10.2147/DMSO.S82338. eCollection 2015.

Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism.

Fu L1, Li F1, Bruckbauer A2, Cao Q1, Cui X1, Wu R1, Shi H1, Xue B1, Zemel MB2.

Author information

Abstract

PURPOSE: 

Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide-cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects.

METHODS: 

We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO) mice.

RESULTS: 

Leucine (0.5 mM) exhibited significant synergy with subtherapeutic doses (0.1-10 nM) of PDE5-inhibitors (sildenafil and icariin) on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet). However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet) for 6 weeks reduced fasting glucose (38%, P<0.002), insulin (37%, P<0.05), area under the glucose tolerance curve (20%, P<0.01), and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis.

CONCLUSION: 

These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine-PDE5 inhibitor combinations.

 

Edited by lostfalco, 25 March 2016 - 09:47 PM.

[Bluecheer]

Hey sorry to my previous comment, i was referring to how long you would cycle mk677 for

[magta39]

 

This is just beautiful! I used this combo for a bit (as part of The God Stack) and highly recommend it (along with intranasal insulin). 

 

Risk Level: high, but not ridiculously high

 

leucine (whey protein would almost certainly work) + pde5i (tadalafil, sildenafil, etc.) = increased insulin sensitivity and fat burning

 

Note the use of subtherapeutic doses! Remember the theory behind The God Stack: MANY small enhancements from numerous different angles adds up to more than the sum of the parts. 1 + 1 + 1 + 1 + 1 = 1,000

 

https://www.ncbi.nlm...pubmed/25999751

 

Diabetes Metab Syndr Obes. 2015 May 6;8:227-39. doi: 10.2147/DMSO.S82338. eCollection 2015.

Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism.

Fu L1, Li F1, Bruckbauer A2, Cao Q1, Cui X1, Wu R1, Shi H1, Xue B1, Zemel MB2.

Author information

Abstract

PURPOSE: 

Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide-cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects.

METHODS: 

We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO) mice.

RESULTS: 

Leucine (0.5 mM) exhibited significant synergy with subtherapeutic doses (0.1-10 nM) of PDE5-inhibitors (sildenafil and icariin) on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet). However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet) for 6 weeks reduced fasting glucose (38%, P<0.002), insulin (37%, P<0.05), area under the glucose tolerance curve (20%, P<0.01), and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis.

CONCLUSION: 

These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine-PDE5 inhibitor combinations.

 

 

Very interesting...I am thinking galantamine may synergize with this...what do you think Lostfalco?  BTW my post workout drink has been 3 scoops whey protein, some citrulline malate powder, one or two drops tadalafil.

 

[lostfalco]

Very interesting...I am thinking galantamine may synergize with this...what do you think Lostfalco?  BTW my post workout drink has been 3 scoops whey protein, some citrulline malate powder, one or two drops tadalafil.

 

Hey magta, yep they should synergize. Tadalafil enhances brain microcirculation and should improve delivery of galantamine to the brain. 

[lostfalco]

And was wondering if there was any risk of consuming too many antioxidants before lasering?

Now I have high cholestrol, wouldn't simply increasing my mitochondria a high amount... Increase the rate at which mitochondria transfers cholestrol Into steroid hormones, or am I missing something?

 

And I'm wondering if pregnelone supplementation would at all trouble the amount that my body naturally makes pregnelone .. For the same reasons to raise testorone and turn cholestrol into hormones.

 

No problem, Bluecheer. =)

 

1. No risk...but the antioxidants might lessen the effects of LLLT.

2. High blood cholesterol doesn't automatically mean that you'll get more cholesterol into your mitochondria. Mitochondrial biogenesis is generally a good thing though and it might help. 

3. There is no evidence in the literature of pregnenolone supplementation inhibiting natural pregnenolone production. It's been tested at very high doses (up to 500mg) in humans for long periods of time (3+ years) with no complications upon cessation. 

Edited by lostfalco, 27 March 2016 - 02:03 AM.

[lostfalco]

What do you guys think about nilotinib?

 

Also I'm scared past DPH use has hurt my cognition.  

http://www.dddmag.co...olinergic-drugs

Hey bigyellow, I've only glanced at the literature on nilotinib so I don't have a strong opinion on it atm. 

 

I'm familiar with the connection between diphenhydramine and increased dementia risk. I'll have to read back through the statistics to see exactly how much it raised the risk. Remember, sometimes articles will say, "Dementia Risk TRIPLES!"...and what that really means is that the risk went from 1 in a billion to 3 in a billion. I'm NOT necessarily saying that's the case with diphenhydramine but I'll have to check when I have some time. My guess though is that you're most likely fine. =)

[lostfalco]

About to consider tb-500 intranasal... Anyone know about bioavailability?

Hey macropsia, tbh I've been unable to find anyone who's ever taken it intransally. We're pretty much shooting in the dark on this one. If you try it let me know what you find. I've noticed a bit from it so far (I think) but it's hard to say. 

[bigyellowlemon]

http://www.ncbi.nlm....les/PMC3255357/

http://www.ncbi.nlm....pubmed/21879386

 

Chitosan seems to increase absorption. Available and cheap too.

[lostfalco]

Interesting. For myself, I don't really see the use his device, but its still an good watch. 

 

 

Thanks for the video, Nuke. He said someday insulin may be used as a smart drug...well, that day is today. ha

[resveratrol_guy]

All, with regards to LLLT, I have a few questions... I can see the LEDs as red, when they're supposedly 850 nm, which is supposed to be infrared and thus invisible to humans. Is this because: (1) 850 nm is actually not invisible; (2) the LEDs are not monochromatic, and I'm seeing the "smear" of the distribution at some lower wavelength; or (3) I'm a mutant who can see near infrared? BTW I allow my 48-LED array to heat up for half an hour before starting a session. This helps to ensure more uniform infrared dosimetry around the skull, as presumably the entire metal encasement is radiating, although perhaps in the far infrared. On the minus side, it sort of burns when I first apply it. Is this a wise practice on my part, or not?

Secondly, as to intranasal insulin, would we not be better off taking oxaloacetate, which should systemically improve insulin sensitivity and dampen insulin spikes, while simultaneously supercharging the citric acid cycle, thereby achieving similar short term cognitive effects as intranasal insulin, while presumably reducing the risk of T3D instead of increasing it (over the longterm)? Furthermore, a paper recently came out indicating that oxaloacetate upregulates SIRT1 in vitro in neurons, among other interesting targets, which may explain its role in life extension of primitive worms, and in any event sounds desirable from a cognitive health perspective. (I would be remiss not to mention the likely risk of islet cell hyperplasia, which might occur in as little as a few weeks of consistent use; however, I'm substantially convinced at this point that oxaloacetate actually decreases the risk of insulinoma specifically and pancreatic cancer generally, if for no other reason than that improved glucose management counteracts these risks due to better protection of pancreatic mitochondria; if you disagree, please provide evidence.)

Edited by resveratrol_guy, 27 March 2016 - 01:51 PM.

[lostfalco]

http://www.ncbi.nlm....les/PMC3255357/

http://www.ncbi.nlm....pubmed/21879386

 

Chitosan seems to increase absorption. Available and cheap too.

Very nice find, bigyellowlemon! Thanks for the studies. This def seems like something worth looking into. Much appreciated.

[lostfalco]

All, with regards to LLLT, I have a few questions... I can see the LEDs as red, when they're supposedly 850 nm, which is supposed to be infrared and thus invisible to humans.  

 

Is this a wise practice on my part, or not?

Secondly, as to intranasal insulin, would we not be better off taking oxaloacetate...

Hey resveratrol_guy, good questions. 

 

1. 850nm light is (barely) visible to the naked eye. Your LEDs should have a faint red glow. 

2. The pre-heating is unnecessary. It's the wavelength and intensity of photons emitted from the LEDs that matter most and they should be the same in minute one as they are in minute thirty. 

3. Oxaloacetate is a VERY interesting substance imo...but it has a different moa than intranasal insulin. There are insulin receptors and a subsequent transduction cascade in the brain that contribute significantly to the effects in healthy and impaired humans. 

 

[Nuke]

850nm is slightly visible to most people. Tested infrared security spotlights at the office, the only people that could not see the glow was the two colorblind people in the room.

 

I have read about oxaloacetate a while ago, but if it improves insulin sensitivity, why not take both? That way you will need less insulin, lowering the chances of insulin resistance in the long term. Same reason why I want to start PQQ before IN-insulin and why I want to make sure my Chromium and Vanadium levels are adequate. 

[lostfalco]

Hey sorry to my previous comment, i was referring to how long you would cycle mk677 for

Hey Bluecheer, I've seen MK-677 tested in humans for 12months straight at 25mg/day with no adverse events reported upon cessation. It can be taken for quite a while without significant risk in my humble opinion. 

 

Edited by lostfalco, 27 March 2016 - 06:23 PM.

[lostfalco]

I have read about oxaloacetate a while ago, but if it improves insulin sensitivity, why not take both? That way you will need less insulin, lowering the chances of insulin resistance in the long term. Same reason why I want to start PQQ before IN-insulin and why I want to make sure my Chromium and Vanadium levels are adequate. 

Good point, Nuke. I should have mentioned that. I don't see any problem with taking oxaloacetate and insulin together. PQQ should also combine well with insulin if you think about the role that each play in enhancing metabolism. In fact, all of these should interact extremely effectively with LLLT as well. The prospects for enhancement are actually pretty exciting when you think about it.

 

Here are a couple of pretty good videos describing the role that insulin plays in the body and how it enhances the delivery of glucose into cells (to be used by mitochondria to produce energy) by upregulating membrane glucose transporter expression.   

 

 

 

Edited by lostfalco, 27 March 2016 - 03:50 PM.

[Nuke]

One of the many important reasons we are looking at mitocondrial enhancement is to drive the Na+/K+ pump. We know that an action potential relies sodium outside and potassium inside the cell. So I began wondering if there is any research on potassium and learning. Except for articles like this and this, getting real studies seems to be hard to find. The only thing I could find measurable studies on is potassium 2-(hydroxypentyl) benzoate.

 

Guessing that it was way to low, I started tracking my dietary potassium intake. Since I started I only reached the RDA of 4700mg a day once. For instance, yesterday I only got 2500mg from diet and the day before that 3500mg. IMO it makes no sense in upgrading the power station, the wires, the pumps and the pipes if the dam is empty. So I think supplementing potassium is a good idea.

 

It seems that a 70kg body contains around 140g of potassium. I have no idea if that is an optimum amount, but seeing how dietary deficient most people is, I would guess not. This the reason I bought potassium chloride to test as a salt replacement and supplement. Currently I take 2g a day, giving me just over 1g of K+. I don't think that KCl is necessarily the best form, but it has a lot of potassium by weight and I'm not trying to lower my blood pressure. From what I read, it may take a while to increase the inter cellular K+ concentration, so I'm not rushing it. Maybe I'll add another 500mg - 1g of K+ later via potassium bicarbonate/citrate to balance the acidity of the Cl-.

 

Some things to keep in mind supplementing potassium
http://charles_w.tri...andthiamin.html
http://howirecovered...ding-potassium/

 

Now potassium 2-(1-hydroxypentyl)-benzoate seems like an interesting compound in its own right. I don't know if its just a very good carrier for potassium or if the rest of the molecule does something too. I see that there are patents for other metals bonded to 2-(1-hydroxypentyl)-benzoate, but I can only find studies on potassium's. Maybe its the only compound that works and the patents is just for in case? From what I gather, the lack of potassium can activate cell apoptosis. Another link between diet and dementia?

http://www.ncbi.nlm....pubmed/22329894
http://www.ncbi.nlm....pubmed/24893984
http://www.sciencedi...304394013001109
https://encrypted.go...2332530B1?cl=en

 

 

[Nuke]

Hi Falco, it seems I'm high jacking your thread here

 

http://www.ncbi.nlm....pubmed/26777890

 

 

Neuroscience. 2016 Mar 24;318:157-65. doi: 10.1016/j.neuroscience.2016.01.020. Epub 2016 Jan 14.

Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats.

Pang Y1, Lin S2, Wright C2, Shen J2, Carter K2, Bhatt A2, Fan LW2.

Author information

 

Abstract

Protection of substantia nigra (SN) dopaminergic (DA) neurons by neurotrophic factors (NTFs) is one of the promising strategies in Parkinson's disease (PD) therapy. A major clinical challenge for NTF-based therapy is that NTFs need to be delivered into the brain via invasive means, which often shows limited delivery efficiency. The nose to brain pathway is a non-invasive brain drug delivery approach developed in recent years. Of particular interest is the finding that intranasal insulin improves cognitive functions in Alzheimer's patients. In vitro, insulin has been shown to protect neurons against various insults. Therefore, the current study was designed to test whether intranasal insulin could afford neuroprotection in the 6-hydroxydopamine (6-OHDA)-based rat PD model. 6-OHDA was injected into the right side of striatum to induce a progressive DA neuronal lesion in the ipsilateral SN pars compact (SNc). Recombinant human insulin was applied intranasally to rats starting from 24h post lesion, once per day, for 2weeks. A battery of motor behavioral tests was conducted on day 8 and 15. The number of DA neurons in the SNc was estimated by stereological counting. Our results showed that 6-OHDA injection led to significant motor deficits and 53% of DA neuron loss in the ipsilateral side of injection. Treatment with insulin significantly ameliorated 6-OHDA-induced motor impairments, as shown by improved locomotor activity, tapered/ledged beam-walking performance, vibrissa-elicited forelimb-placing, initial steps, as well as methamphetamine-induced rotational behavior. Consistent with behavioral improvements, insulin treatment provided a potent protection of DA neurons in the SNc against 6-OHDA neurotoxicity, as shown by a 74.8% increase in tyrosine hydroxylase (TH)-positive neurons compared to the vehicle group. Intranasal insulin treatment did not affect body weight and blood glucose levels. In conclusion, our study showed that intranasal insulin provided strong neuroprotection in the 6-OHDA rat PD model, suggesting that insulin signaling may be a novel therapeutic target in broad neurodegenerative disorders.

 

One more reason to use IN-insulin. IIRC we all lose cells capable of making dopamine as we age, most people just never reach an age where it becomes a problem. Thus it may have some anti-aging benefits too.

[lostfalco]

Rodent Study:

Thyroid hormones bind to nuclear thyroid response elements causing the transcription of choline acetyltransferase which upregulates brain acetylcholine levels (see video below for how T4 and T3 work). Good times!

 

Supplemental thyroid hormones can cause your body to downregulate endogenous production and should be supplemented with great caution (if one chooses to try them). Other things to look into include iodine, kelp, selenium, tyrosine, etc. 

T4 https://www.superior...-levothyroxine 

T3 https://www.superior...t3-liothyronine

Note: no affiliation

 

https://www.ncbi.nlm...pubmed/25206902

 

Neural Regen Res. 2014 Apr 15;9(8):864-71. doi: 10.4103/1673-5374.131602.

The synthetic thyroid hormone, levothyroxine, protects cholinergic neurons in the hippocampus of naturally aged mice.

Fu A1, Zhou R1, Xu X1.

Author information

Abstract

The thyroid hormones, triiodothyronine and thyroxine, play important roles in cognitive function during the mammalian lifespan. However, thyroidhormones have not yet been used as a therapeutic agent for normal age-related cognitive deficits. In this study, CD-1 mice (aged 24 months) were intraperitoneally injected with levothyroxine (L-T4; 1.6 μg/kg per day) for 3 consecutive months. Our findings revealed a significant improvement in hippocampal cytoskeletal rearrangement of actin and an increase in serum hormone levels of L-T4-treated aged mice. Furthermore, the survival rate of these mice was dramatically increased from 60% to 93.3%. The Morris water maze task indicated that L-T4 restored impaired spatial memory in aged mice. Furthermore, level of choline acetyltransferase, acetylcholine, and superoxide dismutase were increased in these mice, thus suggesting that a possible mechanism by which L-T4 reversed cognitive impairment was caused by increased activity of these markers. Overall, supplement of low-dosage L-T4 may be a potential therapeutic strategy for normal age-related cognitive deficits.

 

 

Edited by lostfalco, 28 March 2016 - 06:34 PM.

[Jochen]

 

Very interesting...I am thinking galantamine may synergize with this...what do you think Lostfalco?  BTW my post workout drink has been 3 scoops whey protein, some citrulline malate powder, one or two drops tadalafil.

 

Hey magta, yep they should synergize. Tadalafil enhances brain microcirculation and should improve delivery of galantamine to the brain. 

 

 

I have taken an interest in galantamine (Rhonda Patrick and others seems to have taken a very active interest in similar substances as well).

 

Still doing my research, and not even sure what brand I should be taking at this stage. If anyone has a recommendation,, I am all ears.

 

I would probably start with 4mg and might do some tests with up to 8 mg. Good call on combining it with Tadalafil.

[lostfalco]

I have taken an interest in galantamine (Rhonda Patrick and others seems to have taken a very active interest in similar substances as well).

 

Still doing my research, and not even sure what brand I should be taking at this stage. If anyone has a recommendation,, I am all ears.

 

I would probably start with 4mg and might do some tests with up to 8 mg. Good call on combining it with Tadalafil.

 

Hey Jochen, I've been using Powdercity's galantamine. http://www.powdercit...antamine-powder

 

I would def recommend starting low as it can cause nausea at higher doses. 4mg is a good starting point imo. 

[lostfalco]

Umm...I didn't see this one coming! Pretty cool though. 

 

https://www.ncbi.nlm...pubmed/26976670

 

Neuropharmacology. 2016 Mar 11. pii: S0028-3908(16)30087-9. doi: 10.1016/j.neuropharm.2016.03.015. [Epub ahead of print]

Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease.

Köfalvi A1, Lemos C2, Martín-Moreno AM3, Pinheiro BS2, García-García L4, Pozo MA5, Valério-Fernandes Â2, Beleza RO2, Agostinho P6, Rodrigues RJ1, Pasquaré SJ7, Cunha RA8, de Ceballos ML9.

Author information

Abstract

Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of 3H-deoxyglucose uptake in cultured cortical astrocytes and neurons and in acute hippocampal slices; 2) real-time visualization of fluorescently labeled deoxyglucose uptake in superfused hippocampal slices; and 3) in vivo PET imaging of cerebral 18F-fluorodeoxyglucose uptake. We now show that both selective (JWH133 and GP1a) as well as non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX-2, rather than that of FAAH, MAGL or α,βDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, we found the levels of the endocannabinoid, anandamide reduced in the hippocampus of TgAPP-2576 mice (a model of β-amyloidosis), and likely as a consequence, COX-2 inhibition failed to stimulate glucose uptake in these mice. Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents.

 

Edited by lostfalco, 28 March 2016 - 09:58 PM.

[bigyellowlemon]

Rodent Study:

Thyroid hormones bind to nuclear thyroid response elements causing the transcription of choline acetyltransferase which upregulates brain acetylcholine levels (see video below for how T4 and T3 work). Good times!

 

Supplemental thyroid hormones can cause your body to downregulate endogenous production and should be supplemented with great caution (if one chooses to try them). Other things to look into include iodine, kelp, selenium, tyrosine, etc. 

T4 https://www.superior...-levothyroxine 

T3 https://www.superior...t3-liothyronine

Note: no affiliation

 

https://www.ncbi.nlm...pubmed/25206902

 

Neural Regen Res. 2014 Apr 15;9(8):864-71. doi: 10.4103/1673-5374.131602.

The synthetic thyroid hormone, levothyroxine, protects cholinergic neurons in the hippocampus of naturally aged mice.

Fu A1, Zhou R1, Xu X1.

Author information

Abstract

The thyroid hormones, triiodothyronine and thyroxine, play important roles in cognitive function during the mammalian lifespan. However, thyroidhormones have not yet been used as a therapeutic agent for normal age-related cognitive deficits. In this study, CD-1 mice (aged 24 months) were intraperitoneally injected with levothyroxine (L-T4; 1.6 μg/kg per day) for 3 consecutive months. Our findings revealed a significant improvement in hippocampal cytoskeletal rearrangement of actin and an increase in serum hormone levels of L-T4-treated aged mice. Furthermore, the survival rate of these mice was dramatically increased from 60% to 93.3%. The Morris water maze task indicated that L-T4 restored impaired spatial memory in aged mice. Furthermore, level of choline acetyltransferase, acetylcholine, and superoxide dismutase were increased in these mice, thus suggesting that a possible mechanism by which L-T4 reversed cognitive impairment was caused by increased activity of these markers. Overall, supplement of low-dosage L-T4 may be a potential therapeutic strategy for normal age-related cognitive deficits.

 

 

 

 

 

Umm...I didn't see this one coming! Pretty cool though. 

 

https://www.ncbi.nlm...pubmed/26976670

 

Neuropharmacology. 2016 Mar 11. pii: S0028-3908(16)30087-9. doi: 10.1016/j.neuropharm.2016.03.015. [Epub ahead of print]

Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease.

Köfalvi A1, Lemos C2, Martín-Moreno AM3, Pinheiro BS2, García-García L4, Pozo MA5, Valério-Fernandes Â2, Beleza RO2, Agostinho P6, Rodrigues RJ1, Pasquaré SJ7, Cunha RA8, de Ceballos ML9.

Author information

Abstract

Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of 3H-deoxyglucose uptake in cultured cortical astrocytes and neurons and in acute hippocampal slices; 2) real-time visualization of fluorescently labeled deoxyglucose uptake in superfused hippocampal slices; and 3) in vivo PET imaging of cerebral 18F-fluorodeoxyglucose uptake. We now show that both selective (JWH133 and GP1a) as well as non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX-2, rather than that of FAAH, MAGL or α,βDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, we found the levels of the endocannabinoid, anandamide reduced in the hippocampus of TgAPP-2576 mice (a model of β-amyloidosis), and likely as a consequence, COX-2 inhibition failed to stimulate glucose uptake in these mice. Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents.

 

 

Whoah, cool.

 

 

Edited by lostfalco, 29 March 2016 - 02:58 AM.

[resveratrol_guy]

 

1. 850nm light is (barely) visible to the naked eye. Your LEDs should have a faint red glow. 

2. The pre-heating is unnecessary. It's the wavelength and intensity of photons emitted from the LEDs that matter most and they should be the same in minute one as they are in minute thirty. 

3. Oxaloacetate is a VERY interesting substance imo...but it has a different moa than intranasal insulin. There are insulin receptors and a subsequent transduction cascade in the brain that contribute significantly to the effects in healthy and impaired humans. 

 

Thanks for these concise answers and the visual aids, as always! I'm intrigued by Nuke's suggestion that we coadminister oxaloacetate with intranasal insulin. In theory, if we can hit the right balance, it's the best of both worlds. Fortunately, according to Alan Cash, the FDA forced him to perform toxicity tests with the stuff, and he was never able to find such a threshold. So perhaps it's just a matter of titrating the insulin dose...

 

BTW anyone supplementing chromium should be aware of these graphs (at bottom) comparing Chinese plasma metal ion concentrations in Alzheimers and control subjects. Notice how the relationship between chromium, nickel, and cobalt is starkly different between the groups. This was discussed here.

Edited by resveratrol_guy, 29 March 2016 - 03:35 AM.

[Bluecheer]

 

This is just beautiful! I used this combo for a bit (as part of The God Stack) and highly recommend it (along with intranasal insulin). 

 

Risk Level: high, but not ridiculously high

 

leucine (whey protein would almost certainly work) + pde5i (tadalafil, sildenafil, etc.) = increased insulin sensitivity and fat burning

 

Note the use of subtherapeutic doses! Remember the theory behind The God Stack: MANY small enhancements from numerous different angles adds up to more than the sum of the parts. 1 + 1 + 1 + 1 + 1 = 1,000

 

https://www.ncbi.nlm...pubmed/25999751

 

Diabetes Metab Syndr Obes. 2015 May 6;8:227-39. doi: 10.2147/DMSO.S82338. eCollection 2015.

Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism.

Fu L1, Li F1, Bruckbauer A2, Cao Q1, Cui X1, Wu R1, Shi H1, Xue B1, Zemel MB2.

Author information

Abstract

PURPOSE: 

Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide-cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects.

METHODS: 

We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO) mice.

RESULTS: 

Leucine (0.5 mM) exhibited significant synergy with subtherapeutic doses (0.1-10 nM) of PDE5-inhibitors (sildenafil and icariin) on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet). However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet) for 6 weeks reduced fasting glucose (38%, P<0.002), insulin (37%, P<0.05), area under the glucose tolerance curve (20%, P<0.01), and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis.

CONCLUSION: 

These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine-PDE5 inhibitor combinations.

 

I'm wondering why you consider this a 'High' risk factor, it seems quite safe?

 

[lostfalco]

I'm wondering why you consider this a 'High' risk factor, it seems quite safe?

 

 

I think it's pretty safe too but PDE5i + intranasal insulin + leucine hasn't really been tested that I'm aware of. Taken individually, though, they are each pretty low risk. 

[lostfalco]

Again, extreme caution should be exercised when modulating thyroid hormones...but this was very interesting. 

 

Rodent TBI Model, exogenous T3 administration:

T3 is anti-inflammatory. 

T3 upregulates BDNF and GDNF. 

T3 enhanced functional recovery after TBI.

 

https://www.ncbi.nlm...pubmed/23313345

 

Pharmacol Res. 2013 Apr;70(1):80-9. doi: 10.1016/j.phrs.2012.12.009. Epub 2013 Jan 8.

Exogenous T3 administration provides neuroprotection in a murine model of traumatic brain injury.

Crupi R1, Paterniti I, Campolo M, Di Paola R, Cuzzocrea S, Esposito E.

Author information

Abstract

Traumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury. Thyroid hormones are reported to be decreased in patients with brain injury. Controlled cortical impact injury (CCI) is a widely used, clinically relevant model of TBI. Here, using CCI in adult male mice, we set to determine whether 3,5,3'-triiodothyronine (T3) attenuates posttraumatic neurodegeneration and neuroinflammation in an experimental model of TBI. Treatment with T3 (1.2μg/100g body weight, i.p.) 1h after TBI resulted in a significant improvement in motor and cognitive recovery after CCI, as well as in marked reduction of lesion volumes. Mouse model for brain injury showed reactive astrocytes with increased glial fibrillary acidic protein, and formation of inducible nitric oxide synthase (iNOS). Western blot analysis revealed the ability of T3 to reduce brain trauma through modulation of cytoplasmic-nuclear shuttling of nuclear factor-κB (NF-κB). Twenty-four hours after brain trauma, T3-treated mice also showed significantly lower number of TUNEL(+) apoptotic neurons and curtailed induction of Bax, compared to vehicle control. In addition, T3 significantly enhanced the post-TBI expression of the neuroprotective neurotrophins (BDNF and GDNF) compared to vehicle. Our data provide an additional mechanism for the anti-inflammatory effects of thyroid hormone with critical implications in immunopathology at the cross-roads of the immune-endocrine circuits.

 

[lostfalco]

I've mentioned this before, but I don't think a quick reminder about the connection between the cholinergic anti-inflammatory pathway, galantamine, and insulin will hurt anything. =)

 

https://www.ncbi.nlm...pubmed/26262991

 

PLoS One. 2015 Aug 11;10(8):e0134648. doi: 10.1371/journal.pone.0134648. eCollection 2015.

Antidiabetic Effect of Galantamine: Novel Effect for a Known Centrally Acting Drug.

Ali MA1, El-Abhar HS2, Kamel MA3, Attia AS4.

Author information

Abstract

The cholinergic anti-inflammatory pathway is one of the putative biochemical pathways that link diabetes with Alzheimer disease. Hence, we aimed to verify the potential antidiabetic effect of galantamine, unveil the possible mechanisms and evaluate its interaction with vildagliptin. The n5-STZ rat model was adopted and the diabetic animals were treated with galantamine and/or vildagliptin for 4 weeks. Galantamine lowered the n5-STZ-induced elevation in body weight, food/water intake, serum levels of glucose, fructosamine, and ALT/AST, as well as AChE in the tested organs. Moreover, it modulated successfully the lipid profile assessed in serum, liver, and muscle, and increased serum insulin level, as well as % β-cell function, in a pattern similar to that of vildagliptin. Additionally, galantamine confirmed its antioxidant (Nrf2, TAC, MDA), anti-inflammatory (NF-κB, TNF-α, visfatin, adiponectin) and anti-apoptotic (caspase-3, cytochrome c) capabilities by altering the n5-STZ effect on all the aforementioned parameters. On the molecular level, galantamine/vildagliptin have improved the insulin (p-insulin receptor, p-Akt, GLUT4/GLUT2) and Wnt/β-catenin (p-GSK-3β, β-catenin) signaling pathways. On almost all parameters, the galantamine effects surpassed that of vildagliptin, while the combination regimen showed the best effects. The present results clearly proved that galantamine modulated glucose/lipid profile possibly through its anti-oxidant, -apoptotic, -inflammatory and -cholinesterase properties. These effects could be attributed partly to the enhancement of insulin and Wnt/β-catenin signaling pathways. Galantamine can be strongly considered as a potential antidiabetic agent and as an add-on therapy with other oral antidiabetics.

 

https://www.ncbi.nlm...les/PMC4749496/

 

Mol Med. 2015 Aug 17. doi: 10.2119/molmed.2015.00142. [Epub ahead of print]

Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Non-Obese Diabetic Mice.

Hanes WM1,2, Olofsson PS1, Kwan K1, Hudson LK1, Chavan SS1, Pavlov VA1, Tracey KJ1.

Author information

Abstract

Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic β cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG), interleukin-4 and -6 (IL-4 and IL-6) during KLH-challenge ex vivo. Administration of galantamine beginning at one month of age in non-obese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach.

 

Edited by lostfalco, 31 March 2016 - 09:50 PM.

[lostfalco]

http://www.ncbi.nlm....pubmed/21239433

 

Endocrinology. 2011 Mar;152(3):836-46. doi: 10.1210/en.2010-0855. Epub 2011 Jan 14.

Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance.

Wang X1, Yang Z, Xue B, Shi H.

Author information

Abstract

Obesity is associated with a chronic inflammatory state characterized by adipose tissue macrophage infiltration and inflammation, which contributes to insulin resistance. The cholinergic antiinflammatory pathway, which acts through the macrophage α7-nicotinic acetylcholine receptor (α7nAChR), is important in innate immunity. Here we show that adipose tissue possesses a functional cholinergic signaling pathway. Activating this pathway by nicotine in genetically obese (db/db) and diet-induced obese mice significantly improves glucose homeostasis and insulin sensitivity without changes of body weight. This is associated with suppressed adipose tissue inflammation. In addition, macrophages from α7nAChR-/- [α7 knockout (α7KO)] mice have elevated proinflammatory cytokine production in response to free fatty acids and TNFα, known agents causing inflammation and insulin resistance. Nicotine significantly suppressed free fatty acid- and TNFα-induced cytokine production in wild type (WT), but not α7KO macrophages. These data suggest that α7nAChR is important in mediating the antiinflammatory effect of nicotine. Indeed, inactivating this pathway in α7KO mice results in significantly increased adipose tissue infiltration of classically activated M1 macrophages and inflammation in α7KO mice than their WT littermates. As a result, α7KO mice exhibit more severely impaired insulin sensitivity than WT mice without changes of body weight. These data suggest that the cholinergic antiinflammatory pathway plays an important role in obesity-induced inflammation and insulin resistance. Targeting this pathway may provide novel therapeutic benefits in the prevention and treatment of obesity-induced inflammation and insulin resistance.

 

Edited by lostfalco, 01 April 2016 - 02:38 AM.

[baptistegia]

Hey guys I would like to experiment with intranasal insulin but wanted to ask lostflaco or the others if the Novolin 70/30 NPH type insulin was safe and recommended to use? I have some around the house so it would be easy

http://diabetesindog...n/Novolin_70/30

Ty