Branched chain amino acids, the ketogenic diet pill, and ketosis

Recently I have been combining exogenous ketones with BCAAs on my restricted protein ketogenic diet protocol to see how I react over time. Nutritional ketosis produces an increased ratio of plasma branched chain amino acids to aromatic amino acids which is one of its main proposed mechanisms of action for seizure control. 

It has been suggested that the high ratio of plasma BCAAs/ARAAs could be useful for epileptics as it results in decreasing ARAAs- (ARAAs supposedly increase the excitability potential of the brain entering the central nervous system (Jirapinyo et al., 2004)). This shift resulting in a rise of BCAAs to ARAAs means that a state of ketosis will decrease the excitability potential of the brain and increase seizure threshold. The brain becomes more resilient to stress you could say and brain chemistry in general is more balanced as a result. I feel pretty good today but its just one day, one experiment, and the type I am taking also includes resveratrol and L-carnitine (which may have its own benefits). Resveratrol readily crosses the blood brain barrier and modulates the Wnt signalling pathway to impair glioma stem cell proliferation and inhibit angiogenesis (Cilibrasi et al., 2017)) 

I have been taking the BCAAs at the same time as my exogenous ketones because I have held the belief for a while now that exogenous ketones could improve drug delivery to the brain (much like the combination of aspirin and caffeine) and research already suggests that brain amino acid metabolism is more efficient in a ketotic state (Yudkoff et al., 2007). 

These branched chain amino acids compliment ketogenesis nicely and leucine and lysine in particular are strictly ketogenic amino acids which have shown potent anticonvulsant effects. Its complicated, I know, and the ratio of individual amino acids are important, so I'm still learning and testing blood ketones and blood glucose to assess efficacy.

I am particularly interested in this amino acid supplement from Dr. Heinz Reinwald, who has used it in some very interesting studies for the metabolic management of cancer and to compliment immunotherapy treatments such as in the study below.

Amino acid product and study:

https://www.drreinwald.de/fileadmin/media/downloads/MAP-Product_Info-Basic-E-Web.pdf


http://thescipub.com/abstract/10.3844/ajisp.2016.91.98

IMG- Glucogenic and Ketogenic amino acids:
https://en.wikipedia.org/wiki/Gluconeogenesis

The effects of all this, and nutritional ketosis in general, can be similar to that of the 'ketogenic diet pill' developed by researchers in Japan. The drug, sitipentol, works primarily by enhancing central Gaba neurotransmission and by inhibiting lactate dehydrogenase, an important enzyme involved in the energy metabolism of neutrons (Sada et al., 2015). 

IMPORTANT!!! In cancer, lactate dehydrogenase expression is enhanced as a result of the Warburg Effect (Hirschhaeuser, Sattler, and Mueller-Klieser, 2011) so sitipentol could indeed be very useful not just for seizure control of drug resistant epilepsy, but also to compliment a metabolic protocol for cancer management to take advantage of this metabolic defect. 

IMG- Targeting Lactate Dehydrogenase A inhibits tumourigenesis and tumour progression in mouse models:
(Xie et al., 2014)

The side effects could be irritating, as with other anticonvulsants, but if you have active cancer the pay-off would be worth it in my opinion and I would take the drug in a heartbeat if I ever have a recurrence. It could be taken in cycles. I have back up plans as I have mentioned a few times, and this is near the top of my list of things I would add to my protocol to hit the cancer hard if the situation arises (hopefully not). 

I believe it would likely be effective at therapeutic doses that go beyond seizure control. I would even be more comfortable taking stiripentol than metformin for brain cancer management even though I think they both show great potential. I would simply be more confident of stiripentol offering the specific neurological effects I would be hoping for despite the side effects. I am not entirely convinced that metformin crosses the blood brain barrier at appreciable amounts despite its ability to lower blood glucose so I see sitipentol as being potentially more suitable for brain cancer specifically in theory. It just makes sense to me.

Stiripentol by Diatomit enhances beneficial effects of the therapeutic ketosis for cancer management by inhibiting lactate dehydrogenase and offers neuroprotection and increased seizure threshold by enhancing central Gaba neurotransmission: http://www.diacomit.eu/en/64-check

I had already undertaken extensive research into leucine after learning about its very promising results for drug resistant epilepsy in animals. I wrote a long article on this a while ago, but it was deleted which is a little frustrating, however there is a decent summation here of the potential of these ketogenic amino acids, even in isolation for seizure control.- https://www.epilepsy.org.uk/news/news/amino-acid-good-rescue-medication-64819

Supplementation with L-carnitine may be especially useful for patients taking valproic acid (Epilim) as an anticonvulsant because it can result in hormonal dysregulation in both females AND males. These effects in males are rarely documented or even discussed. Men taking VPA display significantly lower free carnitine/total carnitine but it also makes your sperms weaker swimmers (lower motility), lowers testosterone, and raises insulin and C-peptide concentrations (YIKES!) (Røste et al., 2005). 

Carnitine also aids fatty acid metabolism of course being an essential cofactor required for long chain fatty acids to enter mitochondria. It aids oxidation of palmitic acid (Seim, Kiess and Richter, 2002) so one could potentially argue (I don't know, just a theory) that maybe that if this palmitic acid is used and not stored as body fat (which would promote systemic inflammation), that these studies suggesting palmitic acid promotes carcinogenesis (Pasqual et al., 2017) may be invalidated from a well constructed dietary perspective. It is also worth noting that the study looked at CD36, which is a fatty acid receptor for oxidised low density lipoprotein (the 'bad' cholesterol), which is often linked to atherosclerosis (Endemann et al., 1993) and shouldn't be a problem on a well structured ketogenic diet. Quite the opposite in fact.

IMG- Oxidation of fatty acids: carnitine (Flanagan et al., 2010)

People have different opinions on this, and it is likely that it is actually the ratio of LDL cholesterol and HDL cholesterol is more important or simply HDL on its own (if its too low this is the main problem it seems). On a well structured ketogenic diet LDL cholesterol is unlikely to change much (it may be a little elevated but particle size is the important consideration) but high density lipoprotein (the 'good' cholesterol), usually increases and insulin is normalised. 

This would mean that CD36 is unlikely to be expressed to respond, forming a 'foam cell' as shown below. This is called a foam cell because macrophages are recruited to the location of these fatty deposits on blood vessel cell walls. It is a pro-inflammatory response causing the cell to be filled with lipids and this action creates a 'foamy' appearance. 

IMG- Foam Cell https://en.wikipedia.org/wiki/Foam_cell

A well structured ketogenic diet is anti-inflammatory and also is unlikely to increase thrombosis and platelet aggregation. Risk factors for cardiovascular disease for example are actually improved being on a ketogenic diet, as is the lipid profile as a result. The ketogenic diet improves triglyceride levels, HDL, and LDL particle size- measures that have been seen as indicating risk. More information with a comprehensive list of references can be found here:

http://www.ketotic.org/2013/09/the-ketogenic-diet-reverses-indicators.html

IMG- (Lüscher et al., 2014)

IMG- https://www.spectracell.com/clinicians/products/lpp/

The ketogenic diet is about using fat for energy and it is excess carbohydrates and trans fats which will cause this type of fat to be stored, creating inflammatory responses. I remain unconvinced that palmitic acid from foods such as ghee and coconut oil will promote carcinogenesis, especially when the fatty acid profile is balanced appropriately and the diet is personalised. Palmitic acid from grass fed and grain fed animals may also be different of course, just a thought. I am no expert of course (I'm always learning, nobody is a true expert), but the basic idea seems to make sense to me.

IMG- (St-Pierre et al., 2017)

Other anti-epileptic drugs have similar issues. As with everything though, it is always my belief that we can adjust these variables to bring endocrine functioning back to normal parameters AND allow the drugs to do exert their positive effects IF it is working for the patient to maintain seizure control. I was on VPA (Epilim) at one point when I took AEDs, and it does have survival benefits, but it is my firm belief that any micronutrient deficiencies the medication causes and any negative hormonal responses must be accounted for to achieve the best results not only for seizure control, but also quality of life and potential survival for improved survival.

Maybe I'll have amazing cognitive abilities and be superhuman in some way. It would be good to just feel more normal as I still feel like crap a lot of the time. Telekinesis would be pretty fun though or the ability to read a whole book on a complicated subject in a single day. Kind of like Doctor Strange, that was a cool film, enjoyed it. I like superheroes with intelligence rather than the meathead types.

IMG- http://www.twincities.com/2016/11/03/doctor-strange-review/

References:

Acharjee, S., Boden, W.E., Hartigan, P.M., Teo, K.K., Maron, D.J., Sedlis, S.P., Kostuk, W., Spertus, J.A., Dada, M., Chaitman, B.R. and Mancini, G.J., 2013. Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: a post-hoc analysis from the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation). Journal of the American College of Cardiology, 62(20), pp.1826-1833.

Cilibrasi, C., Riva, G., Romano, G., Cadamuro, M., Bazzoni, R., Butta, V., Paoletta, L., Dalprà, L., Strazzabosco, M., Lavitrano, M. and Giovannoni, R., 2017. Resveratrol Impairs Glioma Stem Cells Proliferation and Motility by Modulating the Wnt Signaling Pathway. PLOS ONE, 12(1), p.e0169854.

Endemann, G., Stanton, L.W., Madden, K.S., Bryant, C.M., White, R.T. and Protter, A.A., 1993. CD36 is a receptor for oxidized low density lipoprotein. Journal of Biological Chemistry, 268(16), pp.11811-11816.

Flanagan, J.L., Simmons, P.A., Vehige, J., Willcox, M.D. and Garrett, Q., 2010. Role of carnitine in disease. Nutrition & metabolism, 7(1), p.30.

Hirschhaeuser, F., Sattler, U.G. and Mueller-Klieser, W., 2011. Lactate: a metabolic key player in cancer. Cancer research, 71(22), pp.6921-6925.

Jin, J.X., Lee, S., Taweechaipaisankul, A., Kim, G.A. and Lee, B.C., 2017. Melatonin regulates lipid metabolism in porcine oocytes. Journal of Pineal Research, 62(2).

Jirapinyo, P., Kankirawatana, P., Densupsoontorn, N., Thamonsiri, N. and Wongarn, R., 2004. High plasma branched-chain amino acids: aromatic amino acids ratio in children on the ketogenic diet: a mechanism in controlling epilepsy. JOURNAL-MEDICAL ASSOCIATION OF THAILAND, 87(4), pp.432-437.


Lüscher, T.F., Landmesser, U.L.F., von Eckardstein, A. and Fogelman, A.M., 2014. High-density lipoprotein. Circulation research, 114(1), pp.171-182.

Pascual, G., Avgustinova, A., Mejetta, S., Martín, M., Castellanos, A., Attolini, C.S.O., Berenguer, A., Prats, N., Toll, A., Hueto, J.A. and Bescós, C., 2017. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature, 541(7635), pp.41-45.

Prospective Studies Collaboration, 2007. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. The Lancet, 370(9602), pp.1829-1839.

Røste, L.S., Taubøll, E., Mørkrid, L., Bjørnenak, T., Saetre, E.R., Mørland, T. and Gjerstad, L., 2005. Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy. European journal of neurology, 12(2), pp.118-124. Sada, N., Lee, S., Katsu, T., Otsuki, T. and Inoue, T., 2015. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science, 347(6228), pp.1362-1367. Schwalb, M. et al. 2016. Clinical Observation of a Novel, Complimentary, Immunotherapeutic Approach based on a Ketogenic Diet, Chondroitin Sulfate, Vitamin D3, Oleic Acid and a Fermented Milk and Colostrum Product. American Journal of Immunology. Vol 12(4). pp.91-8. Seim, H., Kiess, W. and Richter, T., 2002. Effects of oral L-carnitine supplementation on in vivo long-chain fatty acid oxidation in healthy adults. Metabolism, 51(11), pp.1389-1391. St-Pierre, V., Courchesne-Loyer, A., Vandenberghe, C., Hennebelle, M., Castellano, C.A. and Cunnane, S.C., 2017. Butyrate is more ketogenic than leucine or octanoate-monoacylglycerol in healthy adult humans. Journal of Functional Foods, 32, pp.170-175. Xie, H., Hanai, J.I., Ren, J.G., Kats, L., Burgess, K., Bhargava, P., Signoretti, S., Billiard, J., Duffy, K.J., Grant, A. and Wang, X., 2014. Targeting lactate dehydrogenase-a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell metabolism, 19(5), pp.795-809.

Yudkoff, M., Daikhin, Y., Melø, T.M., Nissim, I., Sonnewald, U. and Nissim, I., 2007. The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect. Annu. Rev. Nutr., 27, pp.415-430.