Science Round-Up Seconds: 8 Nootropics to Combat Stroke, Alheimer's & Co and Boost Cognitive Performance. Plus: 7 Rarely Thought of Side Effects of High Dose Glutamine.

Effects of infusion times on phenol content of black tea (Ramalho. 2012)

If you have already listened to the podcast of yesterday's Science Round-Up on the Super Human Radio Website (click here if you haven't and wan't to know what the following is all about), I suppose you will not mind that I compiled some of the complex information about "optimal" tea brewing in the illustration to the right (based on Ramalho. 2012). The colored arrows indicate the time-points at which the given compounds in the tea achieved peak values. The exact time point is also given in minutes, so that a 9' in front of the green caffeine and on the left to the green arrow pointing at the 9 min point tells you "it took 9 minutes for the caffeine content to reach it's maximum in the British tea". The graph in the background shows the catechin concentration depending on the infusion time.

Cholinergenic nootropics - What a recent review says

I guess some of you will probably have heard about piracetam or lecithine as purported enhancers of cognitive function. According to a recent review in the Journal of Experimental Pharmacology those two are yet not the most prosing agents:

Eggs are rich in choline which is an essential nutrient and was abundant in the classic BB diets (rear more)

• Piracetam: no cerebroprotective effects in patients who have open heart surgery, but does help on non-open cardiopulmonary bypass surgery (Holinski. 2008), beneficial effects in response to cerbrovascular and cognitive disorders traumatic origin (Malykh. 2010), intravenous piracetam can prevent cognitive deficits in response to anesthesia (Fesenko. 2009)

• Lecitin: does not improve cognitive deficits in patients (Amenta. 2011; Parnetti. 2007)

More promising "nootropics" - specifically in view of what most people do actually expect, when they buy such products.

• Oxiracetam: improves cognitive performance except for patients with dementia (Malykh. 2010)

• Citocoline: general neuroprotective effects (Alvares-Sabin. 2011), improvements in cognitive performance in healthy and patients and patients with dementia (Secades. 2010), helps with cognitive dysfunction in Parkinson's (Vale. 2008), helps with cognitive function in dementia of neurodegenerative and vascular origin (Parnetti. 2007), prevents cognitive decline after a stroke (Alvarez. 2011), improves recovery after stroke (Garcia-Cobos. 2010) 

• Cerebrolysine: produces signifant cognitive improvements in vascular dementia (Guekht. 2011), effective for both cognitive function and behavioral symptoms in Alzheimer's (Alvarez. 2011), promising results in patients with Alzheimer's (Plosker. 2009)

And a couple of things you would not usually associate with nootropics:

• 

  Suggested read: Amino Acids for Super Humans on the effects and differences between the various forms of carnitine (read more).

  Acetyl-L-carnitine: improves cognitive performance in patients with encephalopathy, decreases anxiety and increases general energy and wellness, as well as fatigue and age-related cognitive deficits (Malaguernera. 2008, Liu. 2008),can reduce or block neuronal death in neurodegenerative diseases (Manusco. 2007), helps ammeliorate hyperammonemia (Cagnon. 2007)

• Saffron extract: beneficial effects in mild to modest Alzheimer's  (Akhondzadeh. 2010)

• DHA (fish oil): positive effects on verbal recognition memory in old subjects (Yurko-Mauro. 2010)

Interestingly, the most profound effects appear to be brought about by acetyl-l-carnitine. In that it's worth mentioning that the benefits could still be related to cholinergic mechanisms, since it has long been known that ALCAR can increase the expression of choline acetyltransferase activity in the central nervous system (Taglialatela. 1994). And the latter is, as the name implies, necessary to form the neurotransmitter acetylcholine .

Glutamine probably not suitable for chronic high dose supplementation

Czech scientists warn about the risks of chronic high dose glutamine supplementation. I know that many of you are still too bamboozeled by the "protein for everything and let the liver take care of any glucose demands I may have" theory, of which you could probably argue that it is the bastard child of the standard BB diet with low carb. Maybe the following recently published paper by a scientist from the Charles University in Prague can help cure this "disease" (and your cognitive problems, fatigue and brainfog).

According to Holecek, the chronic ingestion of glutamine / glutamine enriched diets in can lead to...

Figure 1: In the presence of high amounts of glutamine outside of the cell, the glutamine synthesis (GLN) and with it the ammonia detoxification from muscle tissue sucks (Holecek. 2012).

"(1) Alterations in amino acid transport-as GLN shares the transporters with other amino acids, enhanced GLN intake may impair amino acid distribution among tissues and their absorption in the gut and kidneys.

(2) Alterations in GLN metabolism-GLN supplementation may impair synthesis of endogenous GLN and enhance glutamate and ammonia production.

(3) Alterations in ammonia transport-GLN supplementation may impair ammonia detoxification and negatively affect the role of GLN as the carrier of ammonia among tissues.

(4) Abnormalities in aminoacidemia-increased plasma levels of GLN, glutamate, citrulline, ornithine, arginine, and histidine and decreased levels of valine, leucine, isoleucine, glycine, threonine, serine, and proline are reported.

(5) Alterations in immune system-as GLN has immunomodulating properties, the effect of chronic GLN consumption on the immune system needs to be assessed.

(6) Effect on tumor growth-it should be elucidated whether chronic intake of GLN increases the risk of cancer.

(7) Effect of the withdrawal of GLN supplementation-due to the adaptive response of the organism to enhanced GLN consumption, the withdrawal of GLN may enhance the risk of health problems resulting from GLN deficiency." (Holecek. 2012)

Remember the post on the ammonia induced peripheral and central fatigue with high dose chronic BCAAs supplementation?

In view of the fact that some people consumer up to 40g of glutamine regularly, Holecek demands that "long-term studies should be performed" to test the side effects and evaluate whether there is any benefit at all to justify chronic consumption of a GLN-enriched diet.

So, relying on glutamine instead of carbs, as smart as this idea appears to be in the current carbophobia, could actually make you stupid due to the disruption of the intracellular ammonia detoxification, which is not a problem in muscle only, but also in the brain.

In the end, what we are seeing here is just another instance of a disruption in the natural balance of things. Ornithine, citrulline and arginine, for example are involved in the detoxification of ammonia via the urea cycle. They are however not the only bottleneck to the system.

Obviously your liver and kidneys will have to handle the clearance. People with liver problems (or persons taking "supplements" or NSAIDs that may impair the liver function) are therefore particularly prone to hyperammonemic encephalopathy (Kanamori. 1996; Lemberg. 2009)

Bottom line: Glutamine, just like everything else, in moderation and by no means so much that your body runs on glutamine as fuel. Aside from the mentioned amino acids that help the clearance of ammonia from the blood stream, taurine appears to exert a direct protective affect in the brain (Chepkova. 2006), and lactulose (a fermentable carbohydrate) can reduce the ammonia influx from ammonia producing bacteria in the gut (Vince. 1980). So if you want to wear a helmet when you bang your head against the wall, these would be suggested "take supplement B in order to counter the side effects of supplement A" - side effects of a supplement you would not even have to take, by the way (100% bro-logic ;-)

References: 

• Amenta F, Carotenuto A, Fasanaro G, Lanari A, Rea R, Traini E. Preliminary results of Ascomalva trial on the association of donepezil and choline alphoscerate in Alzheimer’s disease with associated cere-brovascular injury. G Gerontol. 2011;59:89–9.
• Akhondzadeh S, Shaf iee Sabet M, Harirchian MH, Togha M. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativusin the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology (Berl). 2010;207:637–643.
• Alvarez XA, Cacabelos R, Sampedro C, et al. Efficacy and safety of cerebrolysin in moderate to moderately severe Alzheimer’s disease: results of a randomized, double-blind, controlled trial investigating three dosages of cerebrolysin. Eur J Neurol. 2011;18: 59–68.
• Alvarez-Sabín J, Román GC. Citicoline in vascular cognitive impair-ment and vascular dementia after stroke. Stroke. 2011;42(Suppl 1): S40–S43.
• Cagnon L, Braissant O. Hyperammonemia-induced toxicity for the devel-oping central nervous system. Brain Res Rev. 2007;56:183–197.
• Chepkova AN, Sergeeva OA, Haas HL. Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment. Neurobiol Dis. 2006 Sep;23(3):512-21.
• Fesenko UA. Piracetam improves children’s memory after general anaesthesia. Anestezjol Intens Ter. 2009;41:16–21. Polish
• García-Cobos R, Frank-García A, Gutiérrez-Fernández M, Díez-Tejedor E. Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci. 2010;299:188–192.
• Guekht AB, Moessler H, Novak PH, Gusev EI; Cerebrolysin Investigators. Cerebrolysin in vascular dementia: improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial. J Stroke Cerebrovasc Dis. 2011;20:310–318. 
• Holecek M. Side Effects of Long-term Glutamine Supplementation. JPEN J Parenter Enteral Nutr. 2012 Sep 18.
• Holinski S, Claus B, Alaaraj N, et al. Cerebroprotective effect of piracetam in patients undergoing coronary bypass surgery. Med Sci Monit. 2008;14:153–15.
• Kanamori K, Ross BD, Chung JC, Kuo EL. Severity of hyperammonemic encephalopathy correlates with brain ammonia level and saturation of glutamine synthetase in vivo. J Neurochem. 1996 Oct;67(4):1584-94.
• Lemberg A, Fernández MA. Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress. Ann Hepatol. 2009 Apr-Jun;8(2):95-102.
• Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008;33:194–203.
• Mancuso C, Bates TE, Butterfield DA, et al. Natural antioxidants in Alzheimer’s disease. Expert Opin Investig Drugs. 2007;16:1921–1931.
• Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue. Arch Gerontol Geriatr. 2008;46:181–19
• Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci. 2008;53: 3018–3025
• Malykh AG, Sadaie MR. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. Drugs. 2010;70:287–31
• Pantoni L. Treatment of vascular dementia: evidence from trials with non-cholinergic drugs. J Neurol Sci. 2004;226:67–70
• Parnetti L, Mignini F, Tomassoni D, Traini E, Amenta F.  Cholinergic precursors in the treatment of cognitive impairment of vascular origin: ineffective approaches or need for re-evaluation? J Neurol Sci. 2007;257:264–269.
• Ramalho SA, Nigam N, Oliveira GB, Alves de Oliveira P, Matos Silva TO, Passos dos Santos AG, Narain N. Effect of infusion time on phenolic compounds and caffeine content in black tea  Food Research International; 13 December 2012 [ahead of print]
• Secades JJ. Citicoline: pharmacological and clinical review. Rev Neurol. 2010;52 Suppl 2:S1–S62.
• Vale S. Current management of the cognitive dysfunction in Parkinson’s disease: how far have we come? Exp Biol Med (Maywood). 2008;233:941–951.
• Vince AJ, Burridge SM. Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose. J Med Microbiol. 1980 May;13(2):177-91.
• Yurko-Mauro K. Cognitive and cardiovascular benefits of docosahexaenoic acid in aging and cognitive decline. Curr Alzheimer Res. 2010;7:190–196.

Vitamin D, PPAR-γ & the Growth of Healthy Body Fat Stores; Betaine & Fat Inflammation; Free HMB & Muscle Protection; DHA Induced Forgetfulness & Statistical Shenanigan

"Is it already 2013? Must be the DHA, I totally forgot."

The SuppVersity or rather my personal figure of the week was and still is 2013. I actually managed to write 2012 instead of 2013 with every damn study in today's installment of On Short Notice that has been published online in the last couple of days. I wonder how long it will take me to get used to it  - that's like a "new year's date jetlag" ;-)

Now, usually the figure of the week has at least something to do with the topics I am writing about, so I decided to add not another figure, but rather some stats, namely the TOP3 SuppVersity posts (by visitors) from the year that still appears to be programed into my system - 2012:

1. "Particle Size & LCAT Analysis Shows: Three Whole Eggs per Day Improve Lipid Profile in Men & Women W/ MetSyn" (read more)
2. "22g Baking Soda 60min Before a Old-School 4 x 12RM Leg Workout Allow for a 22 Rep Volume Increase on Hypertrophy Oriented Squat + Leg Press + Leg Extension Quads Routine" (read more)
3. "Before, After or In-Between? Study Puts Another '?' Behind the Widely Accepted 'Cardio After Weights' Paradigm" (read more)

That's enough for the -12, let's get to the -13 now and take a look at this week's four On Short Notice items on Vitamin D, Betaine, HMB and DHA.

Study shows: Vitamin D helps your body with fat cell differentiation / maturation 

(Nimitphong. 2012) -- Those of you who have been around for a while will probably remember that I had the cheek to actually say that vitamin D3 could actually make you fat, not lean (suggested reads "Vitamin D3 a 'Fat Synthesizer'!?" "Stronger & Leaner of Fatter & Less Muscular w/ Vitamin D"). So in essence the results of the latest study by Nimitphong, MF Holick  et al. are not new (by the way, yep, this is the MF Holick whose brainchild 25-OHD actually is; cf. Holick. 1972):

Figure 1: 25(OH)D₃ promotes the differentiation of human preadipocytes via PPAR-gamma and reduces the release of stored fat by blunting the lipoprotein lipase levels (Nimitphong. 2012)

"In contrast to its inhibitory effects in a mouse preadipocyte cell line, 3T3-L1, 1,25(OH)₂D₃ promoted adipogenesis in primary human preadipocytes as evidenced by the increased expression of adipogenic markers and lipid filling. In addition, we show that 25(OH)D₃ can also promote the differentiation of human adipocytes, most likely via its activation to 1,25(OH)₂D₃. Furthermore, 1,25(OH)₂D₃ also had stimulatory effects on the differentiation of primary mouse preadipocytes. These results suggest that the local metabolism of vitamin D in adipose tissue may regulate the conversion of preadipocytes to adipocytes and hence support the healthy remodeling of human adipose tissue." (Nimitphong. 2012)

And while Holick is clever enough to bring the benefits of this "remodeling" to the forefront, we are dealing here with the exact same effects PPAR-gamma agonists have - not very surprising after all vitamin D3 turned out to be one (see figure 1). They allow the adipose tissue to expand "healthily", to allow to store more fat (and glucose after being converted to fat) without the negative health effects that occur, when the abundant energy is stored in existing adipocytes, until they burst from the seams.

Since I wanted to make this "short news", I will refer you to the red box in the Seabuckthorn post for further insights into the ambiguous effects of PPAR-gamma.

Betaine reduces inflammatory markers expressed by hypoxia (~suffocating) adipocytes

(Olli. 2013) -- You have read about the potential ergogenic effects of betaine aka trimethylglycine (TMG) at the SuppVersity, before. A a recent study from Finnish researchers does now suggest that it can also reduce the release of inflammatory cytokines and adipokines from hypoxic human adipocytes:

Betaine content (in mg/100g) of some common food items (based on Craig. 2004). You should also check some of your ready made supplements. More and more of the preworkout blends for example contain betaine.

"We show that betaine may reduce inflammation in adipose tissue in hypoxia and may therefore potentially help to reduce systemic inflammation and the risk for other obesity-related diseases." (Olli. 2013)

Usually this would be the point to say "Let's see what the real-world results are", but in this case previous epidemiological data has shown that free living healthy individuals

"[...] who consumed >360 mg/d of betaine had, on average, 10% lower concentrations of homocysteine, 19% lower concentrations of C-reactive protein, and 12% lower concentrations of tumor necrosis factor-α [TNF-alpha] than did those who consumed <260 mg/d." (Detopoulou. 2008)

Reason enough to take a look at the different TMG content of various foodstuffs in figure 1 don' you think so? And by the way, I will still keep you up-to-date as far as future developments in betaine research  are concerned (suggested reads: previous posts on betaine).

Free form HMB reduces acute muscle damage in previously resistant trained men

(Wilson. 2013) -- As far as the scientific background of the anti-catabolic effects of beta-Hydroxy-beta-methylbutyrate (HMB) is concerned There are a couple of promising long(er)term studies mostly in elderly individuals, there is the acute response study by Wilson et al. (result only a minor reduction in lactate dehydrogenase activity; Wilson. 2009) and since a couple of days, there is another acute supplementation study from Jacob M. Wilson et al. which differs from the previous one in terms of

Do you remember Volcan's recently published Master Thesis (read more)? In his experiment he analyzed the effects of eccentric leg extensions + HMB supplementation. I wonder if the results would likewise have been statistically significant, if he had chosen the free acid form of HMB.
• the subjects, now previously strength trained young men (21 years) instead of untrained subjects,
• the measured parameters, now serum creatine kinase (CK), urinary 3-methylhistadine (3-MH),
  testosterone, cortisol and perceived recovery status (PRS), and
• the form of HMB, now a free acid instead of the common calcium bound version of HMB

In this acute supplementation scenario, the replacement of the more common, yet slow absorbing 3g of CA-HMB (60-120min to peak plasma levels) with the faster absorbing free acid form (~30 min to peak plasma levels), was probably also the reason that the differences in post exercise creatine kinase levels (marker of skeletal muscle breakdown) did actually reach statistical significance in this "follow up study" (+329% in placebo vs. 104% in FA-HMB).

The notion that the consumption of 3g of FA-HMB can reduce skeletal muscle damage in trained individuals is supported by trend towards lower 3-MH / CK ratios (marker of protein breakdown) a significantly higher perceived recovery status (measured by questionnaires). There were yet no statistical significant differences in the post-exercise cortisol and testosterone responses. 

Does DHA make young women dumb? Or is it too much statistics that does?

(Beton. 2013) -- It sounds strange, but after receiving a 400mg DHA supplement (no EPA) for 50 days the 126 healthy young women who participated in a study that was conducted at the Department of Psychology of the University of Wales Swansea in the UK, were more likely to forget recently acquired information than their 133 peers who had received a soy + maize oil placebo. The scientists are not able to explain this phenomenon:

Figure 2:Took a hell lot of statistical shenanigan to "prove" the significance of the the results ;-)

"That there was a trend for more to be forgotten in both halves of the study supported the view that it was a genuine rather than a chance result, but naturally such a finding requires replication. The failure to find any difference in the ability to recall the names of capitals suggested that there was no problem in retrieving information from long-term memory stores; and so the finding must reflect some other aspect of the memory process. There is, however, in principle, no reason why n-3 fatty acid supplementation may not have both positive and negative influences. " (Benton. 2013)

In this particular study, the only "positive" thing about the DHA supplement, which contained DHASCO(R), a deodorised and bleached oil derived from the microalgae Crypthecodinium cohnii, was however that it did not have any (negative) effects on the other parameters the scientists measured, i.e. differences in mood, reaction times, vigilance or visual acuity. And if I am honest, I am pretty sure the "cognitive decline" is a null-result, as well - if it had real-world significance you would not need to "reanalyze" and "remerge" the data to finally get the one significant effect you'd like to have in any paper.

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That's it for today, but as you all should know by now, there is always more on the SupppVersity Facebook Wall. Recent examples are

• Thank god, scientists stop thinking like tortoises: "Generalisations such as 'live fast, die young' may be too simple to explain the complex processes affecting ageing and lifespan." (read more)
• Korean cabbage kimchi increases nitric oxide production and suppresses inflammation in the aorta of apoE knockout mice, an atherosclerosis model (read more)
• Sports concussions make you dumb: "A total of 27.7% of concussed student-athletes who were symptom-free and returned to baseline on ImPACT at rest exhibited cognitive decline following moderate physical exertion." (read more)

...and since it's (a) Saturday and (b) there are and will soon be more news, I hope you won't get bored within the next 24 hours it may well take for the next "official" SuppVersity post to be written and published.

References:

• Benton D, Donohoe RT, Clayton DE, Long SJ. Supplementation with DHA and the psychological functioning of young adults. Br J Nutr. 2013 Jan;109(1):155-61.
• Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Stefanadis C. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 2008 Feb;87(2):424-30.
• Holick MF, DeLuca HF, Avioli LV. Isolation and identification of 25-hydroxycholecalciferol from human plasma. Arch Intern Med. 1972 Jan;129(1):56-61.
• Nimitphong H, Holick MF, Fried SK, Lee MJ. 25-hydroxyvitamin d(3) and 1,25-dihydroxyvitamin d(3) promote the differentiation of human subcutaneous preadipocytes. PLoS One. 2012; 7(12):e52171.
• Olli K, Lahtinen S, Rautonen N, Tiihonen K. Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes. Br J Nutr. 2013 Jan;109(1):43-9.
• Wilson JM, Kim JS, Lee SR, Rathmacher JA, Dalmau B, Kingsley JD, Koch H, Manninen AH, Saadat R, Panton LB. Acute and timing effects of beta-hydroxy-beta-methylbutyrate (HMB) on indirect markers of skeletal muscle damage. Nutr Metab (Lond). 2009 Feb 4;6:6. doi: 10.1186/1743-7075-6-6.
• Wilson JM, Lowery RP, Joy JM, Walters JA, Baier SM, Fuller JC, Stout JR, Norton LE, Sikorski EM, Wilson SM, Duncan NM, Zanchi NE, Rathmacher J. β-Hydroxy-β-methylbutyrate free acid reduces markers of exercise-induced muscle damage and improves recovery in resistance-trained men. Br J Nutr. 2013 Jan 3:1-7.