Does tryptophan help prevent seizures?

paolomainardi

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ketogenic diet and neuroendocrine response

No I don't think ketogenic diet increases trp/LNAAs, ketogenic diet increases intestinal fats.
Starvation, fats, triglycerids, tryptophan and serotonin are all intestinal stimuli able to promote neuroendocrine response. Different stimuli carry out all the same response in the brain synthesis of neuropeptides as NPY, Leptin and norephineprine.

I reported this hypothesis in:
Med Hypotheses. 2008;70(3):536-9. Epub 2007 Aug 21.

Is the antiepileptic effect of the ketogenic diet due to ketones?

Mainardi P, Albano C.

Department of Neurosciences, Ophthalmology and Genetics, University of Genova,
Via de Toni, 5, 16132 Genova, Italy.

For many years, the ketogenic diet, including recent variants such the
medium-chain triglyceride (MCT) diet, has been used with good clinical results in the management of refractory epilepsies, particularly in children. The
antiepileptic effects of the diet, like the antiepileptic effects of starvation,
have been attributed to accumulation of ketones, and there are experimental data in animal models to support this hypothesis. Recently, new data about the neuroendocrine response to the acute phase reaction (stress) have emerged, indicating involvement of various neuropeptides, including neuropeptide Y (NPY), which is considered as an endogenous anticonvulsant. The release of NPY is also stimulated by nutrients in the gut, particularly fats. Long-chain and, to a greater extent, medium-chain triglycerides, which are components of the medium chain triglycerid diet, stimulate NPY secretion. This effect may explain the improvement in seizure control after starvation, use of the classical ketogenic diet, and use of the MCT diet.

After this paper Kossof, Baltimora center on KD, contacted me and he is in agreement with my idea.

Paolo Mainardi
 
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paolomainardi

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is serotonin dangerous?

Some posts in this forum reported about the dangerous of serotonin in our body.
In spite of the many roles of this neurotransmitter, into intestine, into blood into brain, if we look to the mechanism of his synthesis and realease, we can understand how it's dangerous for our body.
In the brain the synthesis carry out into vesicles into neurons, then, after stimulus vesicles are released out of the body of the neurons, in a little volume, called synaptic cleft, linking two different neurons. In this way serotonin reach the wall of the neuronal membrane where it bonds itself to its receptors. After a bit of time it's released from receptors and it's re-uptaked from the same neuron that had released it and it is put again in vesicles.
The synthesis and release of serotonin in intestine is the same, but it don't released in a little volume, but in blood. However, just arrived in blood, it bonds platelets, in this way the plasma level of free serotonin is keept under control.

All of these mechanisms let us to understand that free serotonin is very dangerous in our body.

In fact, many diseases are linked with an anormal binding to platelets, i.e. migraine. Also autism is characterized from high levels of serotonin.

BBB is not permeable to serotonin, but became permeable to it if serotonin reach high levels, and serotonin crossing BBB is neurotoxic. Of course, serotonin crossing the BBB is not inside vescicles into neurons, it is in the body of neurons. It's quite different.

To potentiate brain serotonin, in the right way, we have to increase the synthesis of serotonin inside vesicles, not to increase serotonin out of them.

The only way to do it is to increase the amount of tryptophan up-taked into the brain. This amount depend on trp/LNAA plasmatic ratio.

Since '50s some papers reported AEDs able to increase brain serotonin, and from '70s was reported that trp injection in blood of animals have an high anticonvulsant effect.
In the same years, clinical studies in human with oral administration of trp carry out controversial results in severe diseases as depression and epilespy, even if they are closed related with serotonin.
In these years we were very closely to solve drug resistance in epilepsy, but Roche group started to suggest oral adminsitration of trp, or OH-trp (there is no difference) to all world: to improve mood, sleep, decrease weigth, and so.
In 80's about 14 million people used trp, but this suggested the idea that trp is not effective.

yes, oral administerd trp is ineffective, because it's not adsorbed by gastro intestinal (GI) system! This was already in gastrointesinal studies, reporting that the better way to increase free amino acid levels in the blood is eating proteins, respect free amino acids. Free amino acids are scarcely adsorbed by GI system, not only, all LNAAs compete with the same carrier, as to BBB.

Among proteins, whey protein produce an higher level of plasmatic free amino acids, because they don't precipitated in acids of stomach, and, reduced to peptides, they freely cross intestinal membrane.

To increase plasmatic trp/LNAA ratio we have to eat a whey protein rich in trp and poor in the other LNAAs. Unfrotunately all proteins of our diet is limited in trp and rich in the other LNAAs.

I found alpha-lactoalbumin (ALAC) with the highest ratio trp/LNAAs, and Markus studies report it able to significant increase plasmatic trp/LNAA ratio.

It's interesting to note how, in spite of the many role of serotonin in our body, the only precursor, trp, is not easy to find in our diet.
Trp/LNAAs is found low in epilepsy, depression, Multiple sclerosis, etc.

It's surprising that the other mammals are able to synthesize trp from fats, human no. From many of us will be very easy to have a lot of trp (from fats :)). Very likely, in his evolution, human had lost the capacity to produce trp in his body. This mean that human eated more trp in his diet respect animals, then was not more important to synthesize it.

Randomly I found a reason of it: when humans stopped to be nomad, picker and hunter and started to be farmer, he start to eat his cereals.

The domesticated cereals have an high amount of trp respect wild cereals, in this way the human diet became more rich in trp than those of animals.

Two factors are important to increase trp brain uptake and its transformation in serotonin, the sun and physical activity.

Into the past the human live in wide open spaces and they have a lot of physical activity, now we live in close spaces and we have few physical activity.
The incidence of many diseases are increasing and pathologies as allergy are increasing in domestic animals, too, that, for less year than our, they are exposed to the same our diet.
 
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About ketones and seizures

Hello Pablo,

My son is on the ketogenic diet for 6 years in July. Classical (LCT) diet, ratio 4:1 and with suppletion of carnitine, calcium, Co-Q10, vit. D and multi vitamins. He has the Lennox Gastaut syndrome and is resistant to AEDs, is med free for 5 years.

I'm not a scientist, only a mom and a ketogenic cook. But in 'real life' we see a significant relationship between adequate ketosis and seizure reduction, including <70% improvement on his EEG. Before the ketogenic diet his EEG showed 90-99% constant epileptic activity and he had many seizures each day (tonic, clonic, tonic-clonic, absences, myoclonics, complex-partial, name it and LGS has it...) 6 Months after starting the diet his EEG showed > 30% epiletic activity and we saw rarely any seizures anymore.

My son is as good as sz free as long blood ketosis is 3.5+, as soon as it's lower we see many seizures breaking through, the lower his ketosis is, the more seizures he has. We've had a long period of structural low ketosis last year, in spite of the diet, and a terrible lot of seizures all day as a result.
We've tried tweaking the diet ratio to 3,5:1 and we've tried using MCT (oil and liquigen) but this made ketosis even lower.
His calory intake was lowered after a Delta Trac (energy) test which showed he was using only 800 cal; so he was not burning all fats but stored them in his body which was causing low ketosis. After adjusting his LCT diet (less calories and less carbs), ketosis went up to 3-4+ and we have seizure control again.

I see it happen: each time he has a seizure we do test his blood for ketones with our home ketone-set, and yes: it's always too low (> 3.5) Sometimes we do skip a meal, ketosis goes up and the seizures are gone again.

We see this relationship between seizures and blood ketones. Measuring urine ketones has proven to be very unrelayable as an indicator of adequate ketosis for seizure prevention.

I'm familiar with Kossof's publications. I've attended the Matthews Friends keto conference in London (nov. 2007) and have talked to him (and Tuschka DuToit) there. After reading the hypothesis below, I would like to know your thoughts about this relationship between low ketosis and the return of seizures as I've experienced with my son.
 
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paolomainardi

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Ketones and ketogenic diet

I'm very happy to read your results on KD. On Autumn '07 at the congress of american society of epilespy a controlled study on KD was shown, KD resulted more effective of AEDs! Kossov put me in contact with this english reasercher.
I know that KD is efficay in the control of seizures more than AEDs.
The idea that ketones were responsable of anticonvulsive effect start at Biblical times, when seizures were treated with starvation.
In 1921, Wilder postulated that the antiepileptic effects of starvation, used since Biblical times to treat seizure disorders and the antiepileptic effects of a 4:1 fat to carbohydrate ratio diet, used by Radcliffe in 1866, is due to ketones. Therefore, he gave to the high fat diet the name of ketogenic diet. In the subsequent years, when the number of AEDs was very limited, this diet was used extensively in epilepsy with reported improvement rates up to 90% in children and 50% in adults.
It's interesting to note that, in '20s, ketones are considered neurotoxic on the basis of their effect on diabetics. In not diabetics ketone levels can increase until a threshold level, after this ketones can cross BBB and they are used by the brain. Normally, brain use sugars, but if this nutrient is not in the diet, our body shyntesize ketones from fats. The BBB carrier system for ketones being active if ketones reach a threshold value, after this, ketone plasma level stop to increase (in not diabetic subjects) and our brain continue its activity thank to ketones. No neurotoxic effect.

Moreover, in those years, the presence of a metabolic factor in the causation of epilepsy was postulated, in agreement with Erasistratus who linked epilepsy to bowel dysfunction in the 3rd century BC. In 1925, Peterman provided the first evidence of a link between epilepsy and depression, and reported a marked improvement in behaviour, a decrease in irritability and an increased interest and alertness in children treated with the ketogenic diet.

Despite the gradual introduction of antiepileptic drugs (AEDs) and the fact that the diet was not as easy to administer as drugs, the ketogenic diet continue to be used in subsequent years with good clinical results. In 1971, Huttenlocher et al. [12] introduced the medium-chain triglyceride (MCT) diet, in an attempt to retain the beneficial effects of the diet while making it less restricted and easier to administer. The clinical response was positive , but the MCT diet could also cause abdominal cramping, vomiting, and diarrhea, resulting at times in poor tolerability. In 1990s there was a revival of the use of ketogenic diet , partly thanks to the Charlie’s foundation, which was set up by the father of a child with epilepsy who had become seizure-free on the diet.
Several hypotheses have been put forward to explain the mechanism of action of ketogenic diet :
• a direct anticonvulsant effect of ketone bodies,
• an effect of cerebral ketone body metabolism resulting in reduced neuronal excitability and
• indirect effects of the ketogenic diet on seizure control.
However, the precise mechanism by which the diet improves seizure control is still unknown.

I'm referee from Elsevier group and still now I receive papers about studies of ketones (i.e Aceton) in experimental models of epilepsy, but the results are controversial.

When an individual is threatened by stress, a series of complex reactions occur in the body which are aimed at providing optimal protection against progression of the disorder. These changes, which are usually summarized under the name of acute phase reaction (APR) , involve the whole body, but especially the central nervous system (CNS), the hypothalamus and the pituitary, which via the so called neuro-endocrine axis activates all the organs in the body, particularly the adrenals, the thyroid, the gonads, the liver, the gut and its mucosa and lymphatic system and also the intestinal flora. Starvation can induce alterations in the activity of neuropeptides, including neuropeptide Y.
In addition to being neuroregulated, NPY release is stimulated by nutrients in the gut. Under normal conditions, the brain-gut axis functions through a strong array of counterbalancing mechanisms maintaining an equilibrium between absorption and secretion that responds to the precise needs of the organism. Animal studies indicate that the antisecretory factor can be induced by certain types of foods. Fats appear to be potent activators of NPY release in the distal segments of the gut. Long-chain, but especially medium-chain triglycerides (MCT) stimulate NPY secretion. Also tryptophan and/or serotonin stimulate NPY synthesis.

Starvation, fats, MCT, trp, serotonin, are different key to obtain the same neuroendocrine response, the increase of the brain synthesis of NPY.

Neuropeptide Y (NPY), a 36 amino acid peptide, is a hormone present in nervous and gastrointestinal tissues. In the gut, NPY is considered to be the major proabsorptive hormone in the small intestine. The proabsorptive effects of NPY have been clearly demonstrated after its administration to humans, and NPY has been proposed as a potential treatment for syndromes involving malabsorption. Its function has been equated with the earlier descriptive concepts of ‘ileal brake’, or ‘colonic brake’,.

Animal and human studies suggest that neuropeptides are involved in epileptogenesis, and NPY has been proposed to act as an endogenous anticonvulsant. Regulation of neuropeptide expression in forebrain neurons can be altered by seizure activity. In rodents, limbic seizures can selectively alter the synthesis and resting levels of several neuropeptides, including enkephalin, dynorphin, cholecystokinin (CCK), and NPY, in discrete components of hippocampal cell circuitries.
The NPY systems in the hippocampus and in the cerebral cortex appear to play a particularly important role in epileptogenesis and epilepsy. Although NPY is distributed broadly throughout the nervous system, seizure-related changes in NPY and NPY-receptor expression are seen mostly in brain areas, such as the hippocampus, which are often involved in the initiation and propagation of epileptic discharges. Furthermore, application of NPY potently and selectively inhibits excitatory synaptic transmission in the hippocampus, making NPY receptors a potential target for the action of new anticonvulsant drugs.


To increase intestinal levels of trp and/or serotonin can be easer than KD.
In '90s I was co-author of papers demosntrating the anticonvulsive effect of antidepressant SSRIs drugs, wronglly believed to be pro-convulsants. Surely SSRIs increase intestinal serotonin, before to reach the brain, and they are used as pro-assorbitive drugs in intestinal diseases. This effect could be due to an increase of intestinal NPY, named intestinal brake. Recently papers report a little difference betwwen NPY in the brain and in intestine, in intestine it's now called PYY.
For many AEDs is reported that they are able to increase trp and/or sertonin in intestine.
Markus reported a whey protein, alpha-lactalbumin, able to increase trp/LNAA plsamatic ratio.

In the Borgolibero post you can read the reference of the results obtained in epilepsy with this protein.

Then, starvation, KD, MCT diet, trp, serotonin, act all on neuroendocrine system, all of them carry out the same effect in the brain, the increase of the endogenous anticonvulsant NPY.

For many years we have studied brain, heart, gut,... separately, but the gut-brain axis could be very important to study.

With the aim to understand because dysfunctions of the gastrointestinal tract is a common occurrence after traumatic brain injury (TBI), gastroenterologists produced TBI in rats and they found a full collapsed intestinal membrana. An structure damage, other than a functional damage, an increase in permeability.

In conclusion, I'm thankful for your proof on efficacy of KD, I believe in it. The role of ketones was an hypothesis of Wilder in 1921, still today is not demonstred. This don't mean that ketone levels don't increase during KD, but ketones tested in animals models of epilepsy are not effective.

In my opinion it's right to monitor ketone levels to be sure of the ketogenic response of diet, in this way it's possible to increase or deacrease tha fats/sugars ratio, but the recent large evidence on acute phase reaction and on the role of neuroendocrine system linkinb intesinal brain with brain, don't have to be lost.
 

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Does Ketosis Matter?Discussion at the 2008 American Epilepsy Society

By Eric Kossoff


Every December, the ketogenic diet research community gathers at the annual meeting of the American Epilepsy Society (AES) to discuss topics related to the ketogenic diet. At this “SIG” (special interest group), which I have coordinated since 2007, approximately 150 attendees will typically present new material, openly disagree, and debate more controversial topics. The AES SIGs are less regulated (and no continuing medical education credit is provided), hence often a more interactive and exciting setting than typical AES sessions. Attendees include neurologists, basic scientists, and dietitians.

This year’s ketogenic diet SIG in Seattle was no exception: a controversial topic was discussed and a lively debate ensued. This year, we had the issue of “Does ketosis really matter?” discussed from three perspectives: a basic science, clinical neurology, and dietitian perspective.

After I gave a brief introduction to the topic, Dr. Mac Burnham from University of Toronto presented his research regarding acetone as an anticonvulsant. He believed that the data does support that ketosis is important for seizure control in animal models, but interestingly not serum beta-hydroxybutyrate (BOH), which is often measured in clinical studies and occasionally by parents. He believed that acetone was the most important ketone in regards to seizure control. There was some disagreement voiced from basic scientists interested in caloric restriction and glucose modulation (as other mechanisms of action for the ketogenic diet) after his presentation.

Next, Dr. Elaine Wirrell from Mayo Clinic in Rochester, Minnesota gave a lecture on whether ketosis matters from a neurologist’s perspective. At this time, only one study by Dr. Gilbert in 2000, reported that higher levels of serum BOH correlated with improved seizure control (and were possibly more accurate than urine ketone measurement). This study, however, has never been replicated or confirmed. She highlighted that the low glycemic index treatment (See May 2007 Keto News) does not lead to significant ketosis, and yet still preliminarily leads to seizure control. Lastly, Dr. Wirrell discussed recent studies, including those on the modified Atkins diet, that ketosis does seem important during the first month…but not afterwards. This evidence seems to suggest that ketosis may be a marker of the metabolic state while on the ketogenic diet (and possibly correlates with early compliance and success), but does not clearly correlate with seizure control.

Lastly, Dr. Liz Neal from the Institute for Child Health in London, travelled across the Atlantic Ocean to present the dietitians’ perspective on this difficult topic. Dr. Neal discussed data from the recently completed randomized controlled trial of the ketogenic diet (See June 2008 Keto News). In this study, the classic (long-chain) triglyceride ketogenic diet led to higher levels of serum ketones at several time points when compared to the medium chain triglyceride (MCT) diet. However, this did not correlate with seizure control and both diets were equivalent. Interesting additional information regarding carnitine and the general lack of correlation with efficacy in her experience was also discussed.

In summary, I think the jury is still out on the role of ketosis in the ketogenic diet. Most basic scientists today believe that it is not the only (or even primary) mechanism of action of dietary therapy (See October 2007 Keto News). As was clear from both Drs. Wirrell and Neal, both child neurologists and dietitians are starting to agree. However, ketosis may be important during the initial several months based on some clinical research.

Topic Editor: Robert Fisher, MD, PhD
Last Reviewed: 1/30/09

Bron: http://www.epilepsy.com/epilepsy/keto_news_feb09
.
 

paolomainardi

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are ketones repsonsable of anticonvulsant effect of KD?

Dear dutch mom,

I'm happy of your results on KD and I believe KD is very effective on epilepsy.
After my paper on medical hypotheses about the role of neuroendocrine (NE) system in the control of seizures with KD, I had some emails with Kossof, who read my paper and he was in agreement with my hypotesis. In fact, still now is controversial the anticonvulsant effect of acetone, and ketosis seem be very important only in the first month of KD.

Wilder linked the anticonvulsant effect of a diet rich in fats and poor in sugars, to ketosis in agreemeent with ketosis induced by starvation. Starvation was used to seizure control at Biblical times.

Today it's well know that starvation, intesinal fats, intestinal triglycerids (above all medium chaun T), intesinal serotonin and intestinal triptophan are all able to produce a NE response, the same NE response: the increasing of the synthesis in the brain of neuropetides, as NPY, norephineprine and leptin.

Some papers report an increase in NPY after trp injection in animals. Injections of NPY directly in the brain, were shown to have a high anticonvulsant effect, NPY is named "endogenous anticonvulsant".

Starvation and KD are not easy to adminstrate. The ame effect can be reached incresing trp and or serotonin in intesine.
Curiosly most of AEDs increase trp and or serotonin in intestine. Antidepressive SSRI drugs increase intesinal serotonin, and today it's well know they have an anticonvulsant effect, too.
Markus's papers report alpha-lactalbumin able to increase trp/LNAA ratio, about 50%!
In Italy an epileptic pt with about 200 seizures/day (absence) in tehrapy with Valproic acid, only decreasing therapy have only 100 seizures day. Then, after modifying his diet, increasing fats and decreasing sugars, the seizures go below 70 in a day. With alpha-lactalbumin the seizures are less than 30 in a day.
 

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Paolo, thanks a bunch for posting your thoughts here. Good stuff.

Are you familiar with the application of gluten free (GFCF) diets for seizures? These diets do not affect the balance of sugar/fat consumption the same as the Ketogenic, LGIT or MAD.

I was wondering if you might review this speculation about the ratio of dietary magnesium to glutamate and see how it fits with your understanding of the way the gut/NPY works.
 

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gluten free diet

I'm thankful for your attention.

gluten free diet is used in celiac disease. It's reported to increase trp/LNAA plasmatic ratio, for example:
Gluten-free diet may alleviate depressive and behavioural symptoms in adolescents with coeliac disease: a prospective follow-up case-series study
Päivi A Pynnönen, Erkki T Isometsä, Matti A Verkasalo, Seppo A Kähkönen, Ilkka Sipilä, Erkki Savilahti, Veikko A Aalberg
BMC Psychiatry 2005 5:14

It's interesting to note that the children of this study suffering of depression, too (3/9) have the lowest trp/LNAA ratio (to understand it, I suggest to read Jobe's paper on J neurochem 2005, linking epilepsy and depression).

Data in literature, and our own data, report low trp/LNAA ratio in blood of epileptic patients, then also in these patients gluten free diet is able to increase this plasmatic ratio. The brain upatke of trp depend on this ratio, the the brain serotonin synthesis (Chugani by PET), and after a lot of days of this increase in trp/LNAA ratio, neuroendocrine system carry out the increasing in the brain NPY synthesis.


In the next I'll answer about Mg, but I remember you that Mg is needed to convert trp in serotonin.

Paolo Mainardi
 

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gluten free diet is used in celiac disease.
It's also increasingly being used (mostly by parents/patients on their own initiative) to treat autism spectrum disorders and seizure conditions. See here for more background on the application for seizures:

GARD (GFCF) diet for seizures

Some GARD diet testimonials

It's reported to increase trp/LNAA plasmatic ratio,
Well, that is interesting. This would appear to be the first real common denominator between the GFCF diets and the Keto/LGIT/MAD diets then.

In the next I'll answer about Mg, but I remember you that Mg is needed to convert trp in serotonin.
Thanks. I'm looking forward to it.
 

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Mg on seizures

Mg play different roles in our body. It inhibits glutamate, it controls taurine metabolism and it is needed to convert trypthophan in serotonin. It's reported to have an antiinflammation effect, too.
But I'm asking: is it Mg, orally administerd, adsorbed by intestine?
About 80% is not adsorbed, it's adsorbed by satuarble carrier system (K. D. Fine et al. Magnesium Absorption, J. Clin. Invest.Volume 88, August 1991, 396-402).
The antiinflammation effect of Mg is reported in intestine, too, then Mg, orally adiminstered, can decrease inflammation in intestine, improving intestinal functions.
Scanlan, B.J., Tuft, B., Elfrey, J.E., Smith, A., Zhao, A., Morimoto, M., Chmielinska, J.J., Tejero-Taldo, M.I., Mak, I.T., Weglicki, W.B., and Shea-Donohue, T. 2007. Intestinal inflammation caused by magnesium deficiency alters basal and oxidative stress-induced intestinal function. Molecular and Cellular Biochemistry. Jul27; Epub ahead of print.

Paolo Mainardi
 

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To increase plasmatic trp/LNAA ratio we have to eat a whey protein rich in trp and poor in the other LNAAs. Unfrotunately all proteins of our diet is limited in trp and rich in the other LNAAs.

I found alpha-lactoalbumin (ALAC) with the highest ratio trp/LNAAs, and Markus studies report it able to significant increase plasmatic trp/LNAA ratio.

It's interesting to note how, in spite of the many role of serotonin in our body, the only precursor, trp, is not easy to find in our diet.
...
It's surprising that the other mammals are able to synthesize trp from fats, human no. From many of us will be very easy to have a lot of trp (from fats :)). Very likely, in his evolution, human had lost the capacity to produce trp in his body. This mean that human eated more trp in his diet respect animals, then was not more important to synthesize it.

Randomly I found a reason of it: when humans stopped to be nomad, picker and hunter and started to be farmer, he start to eat his cereals.

The domesticated cereals have an high amount of trp respect wild cereals, in this way the human diet became more rich in trp than those of animals.

Two factors are important to increase trp brain uptake and its transformation in serotonin, the sun and physical activity.
...
I'd like to revisit these comments. Paolo, when you talk about "human diet" in general terms, are you referring to the standard American diet (SAD), mediteranean diet, vegetarian diet? Diets can vary tremendously as you look at different regions of the world.

If I understood you correctly, a vegetarian diet based on whole grains/cereals/legumes is going to effect a higher trp/LNAA ratio than a SAD with animal proteins and lower consumption of whole grains/cereals/legumes.
 

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the diet

In UE and US a children with down syndrome has an high probability to have epileptic seizerues, Aboiut 50% of adult downs have seizures (vs 1-1.5% in all people). In Asia a Down children has less probability to have epileptic seizures respect all people. This was linked with different diet.
Beacuase all proteins of our diet have few trp and many LNAAs, it's well know that a proteic diet carry out a decrease in trp/LNAA plasmatic ratio. Then proteic diet don't increase brain serotonin. In fact, serotonin synthesis was demonstred by Chugani by Pet to be correlated with the aumount of trp uptaked in the brain that it depend on trp/LNAA plasmatic ratio.
Carbohydrates increase serotonin. In fact, insuline levels result incerased after carbohydrate administration. Insulin remove sugars from blood, but it remove LNAAs, too, but not in the same way. The result is an trp/LNAAs increasing. This increasing is looked for bulimic patients, that they are looking to increase brain serotonin by food.
Unfortunatly to eat carbohydrate carry out an increase in body weight.
To increase brain serotonin by ALAC let to an high decrease of body weight in bulimic pts.
 

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I'm not sure you answered my previous question.

... Carbohydrates increase serotonin. In fact, insuline levels result incerased after carbohydrate administration. Insulin remove sugars from blood, but it remove LNAAs, too, but not in the same way. The result is an trp/LNAAs increasing. ...
The ketogenic diet, modified Atkins diet and LGIT all restrict carbohydrate consumption. How does that fit with your trp/LNAA ratios?

Also, is there a significant difference (in affecting trp/LNAA ratio) between dietary simple carbohydrates and complex carbohydrates?
 

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It is very important question. An high fat diet (KD) is able to control seizures, but also an high carbohydrate diet is reported to be able to control seizuers.
The anticonvulsive effect of carbohidrate diet is surely due to the increasing of trp/LNAA plasamtic ratio, then trp brain uptake increase, this carry out an increase in brain serotonin synthesis (Chugani by PET).
But how is KD able to control the seizures ?
A lot of studies were done on ketnones in experimental models of epilepsy, but controversial results are reported.
As I wrote on medical hypotheses, other than ketones are responsible of anticonvulsant effect of KD.
Weinshenker D. in Epilepsia. 2008 Nov;49 Suppl 8:104-7. write: The purpose of this article is to review the available data considering two classes of molecules that may contribute to the anticonvulsant effect of the KD: norepinephrine and the orexigenic neuropeptides galanin and neuropeptide Y.

In fact, starvation (used as anticonvulsant at Biblical time), fats (KD), Triglycerid, expacially medium chain T (MCT diet) and tryptophan and serotonin (in intestine) are all able to promote the brain synthesis of NPY, norephineprine and other neuropeptides, by neuroendocrine system.
Different keys to obtain the same result.
NPY is named an endogenous anticonvulsant.
The anticonvulsant effect of antidepressant SSRI drugs is due to the intestinal increase of serotonin, many antiepiletic drugs increase intestinal trytophan and or serotonin, alpha-lactalbumin increase trp/LNAA plasmatic ratio (markus CR) of about 50%.
 
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Thanks Paolo. I know you are repeating yourself a little bit, but I'm starting to get my head wrapped around this concept. Let's see if I can summarize this correctly:
  • The body can produce a natural anti-convulsant compound called neuropeptide Y (or NPY).
  • NPY is produced by the neuroendocrine system only when provoked by a sustained stimuli.
  • There are different mechanisms that can stimulate the neuroendocrine system to synthesize NPY:
    1. high trp/LNAA ratio (achieved by supplementing with alpha-lactoalbumin (ALAC), consuming a diet with a high ratio of complex carbs (carbs from whole grains/cereals) to dietary proteins or tryptophan/serotonin supplements [or medications such as SSRIs that increase intestinal trp/serotonin])
    2. high ratio of intestinal fats (achieved by Ketogenic, MAD, LGIT and MCT diets)
    3. starvation
  • Increasing the trp/LNAA ratio to stimulate NPY synthesis (as opposed to starvation or increasing intestinal fats) has the added benefit of increasing brain serotonin synthesis.

The wikipedia page on NPY mentions that leptins inhibits NPY release. I would then expect that increasing leptins would decrease the production of NPY and increase the possibilities for a seizure. However, there was some research published a while back indicating that a leptin diet could help control seizures. Thoughts?

How could someone supplement their diet with ALAC if they wanted to test your trp/LNAA hypothesis? I know that many of the protein powder supplements we can buy in the (vitamin) stores are largely made from whey proteins, but they are not 100% ALAC (they are typically 20-30% ALAC). How much ALAC would one need to eat daily? I assume this would vary depending upon whether one was eating a high carbohydrate, low protein diet or not.
 

paolomainardi

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No problem to repeat me. Furthermore English is not my home language.

NPY is produced by the neuroendocrine system only when provoked by a sustained stimuli.

Not only by stimuli, NPY is essential in the brain, but it need to repair brain damage. In fact NPY is linked to neurogeesis and synaptogenesis.

An amount of NPY is continuosly synthesized in our brain, but when tha brain have the need to repair itself, more NPY is needed.
An right amount of intestinal trp allow a right synthesis of brain NPY. In fact a low trp/LNAA plasmatic ratio is reported in different neurological diseases. Restore aright trp/LNAA ratio carry out to adjuste brain NPY level.

The wikipedia page on NPY mentions that leptins inhibits NPY release.

It's not corrected. Some papers report Leptin increase NPY synthesis, others report NPY increase leptin synthesis. However if there are high levels of NPY there are high levels of leptin and viceversa.
On wikipedia I found: Leptin works by inhibiting the activity of neurons that contain neuropeptide Y (NPY).
small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic.

It's interesting to note that NPY injected in the brain has an high anticonvulsive effect, too.

However, there was some research published a while back indicating that a leptin diet could help control seizures

This confirm the action on NPY. Also trp injected in blood of animals carry out an high anticonvulsive effect,

How could someone supplement their diet with ALAC if they wanted to test your trp/LNAA hypothesis?

In Italy I have registered a food supplement (Serplus) containg ultrapure ALAC. This allow me to study this hypothesis in drug resistant epileptic pts. De Sarro, an italian pharmacologist, ex student of Meldrum, test ALAC in different experimental model of epilepsy. His results, obtained in more than 500 animals, were fantastic. Thank to them, ALAC is entry in the screening of new drugs at NIH.
We adminsitered 2.25 g/die or 4.5 g/die of this protein. Now a controlled trial on Ulvericht-Lundborg epilepsy is running, with very good clinical outcome also int his severe epilepsy.
Thank to some friend living in US, I can send to you some bags of Serplus.

We are working to register Serplus as food supplement in US.

I'm liking to outline that the my main work is research. To register food supplement was the only way to demonstrate my ideas are rights.
The results were better than my best forecasts.
 

paolomainardi

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As you can read in my previous posts, I had looked for ALAC to its serotoninergic effect, but many papers refer about gastrointetsinal effect of ALAC. ALAC in human milk is responsable to start intestinal absorption. In few days after the born the intestinal permeability decrease to let the control of nutrients.
In adults, it's reported the antibacterical role in intestine of three peptides arising from enzymatic demolition of ALAC.
How much it's relevant the action of ALAC on intestine to explain its anticonvulsant effect?

It's well know that seizures increase intestinal permeability, it's reported that laparotomy resolve drug resistant epilepsy
Laparotomy for treatment of seizures Szawarski et al. Emerg Med J.2008; 25: 120

but a very interesting paper of iranian Dehpour report an increasing in seizures in an experimental model of epilepsy in mice treated with croton oil to carry out an intestinal inflammation.

J Gastroenterol Hepatol. 2004 Mar;19(3):270-7.

Intestinal inflammation alters the susceptibility to pentylenetetrazole-induced
seizure in mice.

Riazi K, Honar H, Homayoun H, Demehri S, Bahadori M, Dehpour AR.

Department of Pharmacology, School of Medicine, Tehran University of Medical
Sciences, Tehran, Iran.

Dehpour wrote me he's available to test ALAC in this model. Now I'm starting to determine intestinal permeability in epileptic pts by lactulose/manitol determination in urine after 6 hour of oral administration. In this way I'll determine if ALAC is able to decrease intestinal permeability, while it is controlling seizures.
 
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Ruth

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If I'm understanding you correctly, you are saying that the reason the ketogenic diet works (and, I'm guessing by extension is because they increase the trp/LNAA ratio in the gut? Is reducing dietary intake of simple carbohydrates enough to affect the trp/LNAA ratio?
Hi Paolo, welcome
Bernard made this forum out of love for his wife Stacy. This love extends throughout all of CWE.

I do not completely understand all of this, please answer Bernard's question.

Ruth
 

paolomainardi

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trp/LNAA ratio

The anticonvulsant effect of ketogenic diet it's not linked to trp/LNAA plasmatic ratio.
On trp/LNAA plasmatic ratio depends the trp brain uptake and on the amount of trp uptaked in the brain depends the brain synthesis of serotonin, then on trp/LNAA plasmatic ratio depends brain synthesis of serotonin.

Carbohydrate diet is able to increase trp/LNAA plasmatic ratio:
Møller SE. Neutral amino acid plasma levels in healthy subjects: effect of complex carbohydrate consumed along with protein. J Neural Transm. 1989;76(1):55-63
This serotoninergic effect is the reason of emotional eating: looking to increase trp/LNAAs some people eat a lot of snack to improve their depression.

To increase intestinal trp has an anticonvulsant effect, too, because it controls brain synthesis of neuropeptides, i.e. NPY, named an "endogenous anticonvulsant", leptin and norephineprine.

NPY brain synthesis is stimulated by other intestinal nutrients as serotonin.

It's reported that anticonvulsant drugs are able to increase intestinal trp and/or serotonin. Antidepressant drugs are able to increase intetsinal serotonin, they are used in gastroentherologic diseases, too. At low doses they stop diarrhea, at high doses they start it. Surprisingly at low doses they are anti-convulsants, too, at high doses they are pro-convulsants (Jobe J Neurochem 2005).

Leptin and NPY is striktly linked togheter.
Leptin brain synthesis is stimulated by other intestinal nutrients as fats, then a diet rich in fats, i.e. ketogenic diet, has an anticonvulsant effect.
Not only KD has an anticonvulsant effect:
Van der Auwera I, Wera S, Van Leuven F, Henderson ST. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer's disease. : Nutr Metab (Lond). 2005 Oct 17;2:28.
Zhao Z et al. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci. 2006 Apr 3;7:29.
Siva N. Can ketogenic diet slow progression of ALS?Lancet Neurol. 2006 Jun;5(6):476.
Gasior M, Rogawski MA, Hartman AL Neuroprotective and disease-modifying effects of the ketogenic diet Behav Pharmacol. 2006 Sep;17(5-6):431-9.(on Parkinson's and Alzheimer).

Neuropeptide brain synthesis is stimulated by other intestinal nutrient as triglycerids, mainly medium chain triglycerid. MCT diet is used as KD.

Another way to increase brain neuropeptides is starvation. Stravation was used at Biblical time to treat seizures and starvation is reported in about all religions as able to improve mental health.

In conclusion we have difefrent key to increase brain neuropeptides. They are responsible of neurogenesis and synaptogenesis, then on their brain levels depend the neuronal plasticity: the ability of the brain to repair itself.
The neuronal circuitations have to keept continuisly active, new circuitations have to be performed to repair bad working circuitations.

Brain neuropeptides levels reach the top in the first years of life, then they decrease.

Paolo Mainardi
 

Keith

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There's a lot to learn here, thank you. It seems the missing factor in this thread is gut flora, the friendly and sometimes unfriendly, overgrown microbes. It's the underlying, root problem overlooked in some types of epilepsy. I believe the reason the ketogenic diet works is due to shifting flora. Food changes our intestinal balance, hopefully in the right direction. It's not about ketones. The same mechanism applies to similar diets including gluten-free, low starch diet and specific carbohydrate diet (SCD). Vegan diet also helps many people with digestive issues. The standard American diet feeds the problem: infection of the small intestine, an ulcerative condition where microbial toxins lower seizure threshold while intestinal irritation leads to seizure originating in Peyer's Patches, where the lymphatic system is intimately associated with nerve bundles and fibers directly connected to the brain. The intestines contain the most extensive innervation of the body. Neurology presently treats the problem from the neck up without real regard for gut-brain connection. There are many ways to heal intestines other than diet and it's more art than science these days . . . it's called abdominal epilepsy and there may not be gastrointestinal symptoms making diagnosis difficult.
 
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