Branched chain amino acids and epilepsy

Recent work in a number of laboratories have shown that branched chain amino acids (BCAA’s) alone or in conjunction with the ketogenic diet have antiepileptic properties.  While the mechanism of action for the antiepileptic effect of BCAA’s has not been completely elucidated, a portion of their effect could be by increasing the flux through the gluconeogenic enzyme PEPCK.  Other pages on this site describe PEPCK, present data for how PEPCK regulates epileptiform activity in the hippocampus and proposes a model that unites the anti-epileptic effects of the Ketogenic Diet, triheptanoin and the glycolytic inhibitor 2-deoxyglucose (2-DG).  Like these interventions, the mechanism of action of the branched chain amino acids may be by increasing the flux through PEPCK

When considering human nutrition, the branched chain amino acids we are talking are leucine, isoleucine, and valine.  These amino acids are considered essential to the human diet since they cannot be made from non-protein precursors.  BCAA’s rapidly cross the blood brain barrier, which is not true of all amino acids.  And one of their important roles appears to be in the glumatame/glutamine shuttle between neurons and astrocytes.  In addition, BCCA’s contribute to anaplerosis.  This is especially important under conditions when cellular pyruvate concentrations are low as would be expected during the ketogenic diet.  One of the predictions from my model of the ketogenic diet is that increasing the availability of amino acids in the brain that contribute to anaplerosis would increase the flux through PEPCK and thus increase the efficacy of the diet. 

Here is a nice review of the data from Dr. Evangeliou, including a couple of great figures on the relationship of BCAA's to anaplerosis and the Krebs Cycle


Branched chain amino acids as adjunctive therapy to ketogenic diet in epilepsy: pilot study and hypothesis.

Evangeliou A, Spilioti M, Doulioglou V, Kalaidopoulou P, Ilias A, Skarpalezou A, Katsanika I, Kalamitsou S, Vasilaki K, Chatziioanidis I, Garganis K, Pavlou E, Varlamis S, Nikolaidis N.

J Child Neurol. 2009 Oct;24(10):1268-72. Epub 2009 Aug 17.

A pilot prospective follow-up study of the role of the branched chain amino acids as additional therapy to the ketogenic diet was carried out in 17 children, aged between 2 and 7 years, with refractory epilepsy. All of these patients were on the ketogenic diet; none of them was seizure free, while only 13 had more or less benefited from the diet. The addition of branched chain amino acids induced a 100% seizure reduction in 3 patients, while a 50% to 90% reduction was noticed in 5. Moreover, in all of the patients, no reduction in ketosis was recorded despite the change in the fat-to-protein ratio from 4:1 to 2.5:1. Although our data are preliminary, we suggest that branched chain amino acids may increase the effectiveness of the ketogenic diet and the diet could be more easily tolerated by the patients because of the change in the ratio of fat to protein.

Effects of valine, leucine, isoleucine, and a balanced amino acid solution on the seizure threshold to picrotoxin in rats.

Skeie B, Petersen AJ, Manner T, Askanazi J, Steen PA.

Pharmacol Biochem Behav. 1994 May;48(1):101-3.

Department of Anesthesiology, Rikshospitalet, University of Oslo, Norway.
During infusion of branched-chain amino acids (BCAAs) in humans, changes in ventilatory drive, sleeping pattern, and appetite have been reported. The mechanism by which BCAA exerts their effects on CNS remains unclear. An infusion of a BCAA solution (300 mg/kg) has previously been found to increase the seizure threshold in rats to the proconvulsant drug picrotoxin, an antagonist on the GABA-benzodiazepine receptor complex. In this study, each of the BCAAs given separately (valine, leucine, isoleucine; 300 mg/kg) (n = 10) increased the mean latency time to onset of seizures vs. placebo as an indication of an increased seizure threshold. A balanced amino acid solution (Vamin-Glucose) had no effect on the seizure threshold. Thus, these CNS effects are specific for BCAAs and occur with all three.



Effects of valine, leucine, isoleucine, and a balanced amino acid solution on the seizure threshold to picrotoxin in rats.

Skeie B, Petersen AJ, Manner T, Askanazi J, Steen PA.

Pharmacol Biochem Behav. 1994 May;48(1):101-3.

Department of Anesthesiology, Rikshospitalet, University of Oslo, Norway.
During infusion of branched-chain amino acids (BCAAs) in humans, changes in ventilatory drive, sleeping pattern, and appetite have been reported. The mechanism by which BCAA exerts their effects on CNS remains unclear. An infusion of a BCAA solution (300 mg/kg) has previously been found to increase the seizure threshold in rats to the proconvulsant drug picrotoxin, an antagonist on the GABA-benzodiazepine receptor complex. In this study, each of the BCAAs given separately (valine, leucine, isoleucine; 300 mg/kg) (n = 10) increased the mean latency time to onset of seizures vs. placebo as an indication of an increased seizure threshold. A balanced amino acid solution (Vamin-Glucose) had no effect on the seizure threshold. Thus, these CNS effects are specific for BCAAs and occur with all three.


Modulation of pentylenetetrazol-induced seizure activity by branched-chain amino acids and alpha-ketoisocaproate.

Dufour F, Nalecz KA, Nalecz MJ, Nehlig A.

Brain Res. 1999 Jan 9;815(2):400-4.

Branched-chain amino acids, and mainly leucine act as nitrogen donors in the cerebral glutamate-glutamine cycle, thereby reducing brain excitability. Rats equipped with cortical electrodes received 300 mg/kg of leucine, isoleucine, valine or the ketoacid of leucine, alpha-ketoisocaproate at 2 h before the induction of seizures by 40 mg/kg pentylenetetrazol. Control groups received saline or a commercial mixture of amino acids, Vamine(R). Leucine and isoleucine increased the latency to absence-like and tonic-clonic seizures but did not influence the duration of the tonic-clonic seizure. Vamine(R), valine and alpha-ketoisocaproate had no effect. These data are consistent with the role of leucine in buffering brain glutamate concentration. Copyright 1999 Elsevier Science B.V.



High plasma branched-chain amino acids:aromatic amino acids ratio in children on the ketogenic diet: a mechanism in controlling epilepsy.

Jirapinyo P, Kankirawatana P, Densupsoontorn N, Thamonsiri N, Wongarn R.

J Med Assoc Thai. 2004 Apr;87(4):432-7.

BACKGROUND: The authors proposed that ketogenic diets will produce an increase in the ratio of branched chain amino acids (BCAAs) and aromatic amino acids (BCAAs) in plasma of children who are on the diets. SUBJECTS AND METHOD: A sample of plasma amino acids sample before initiation of fasting and on day 10 of the dietary treatment was obtained in patients with refractory epilepsy who were newly admitted for initiation of ketogenic diet. Plasma amino acids were determined by high performance liquid chromatography equipment. RESULTS: There are 20 patients with refractory epilepsy participating in this study. Outcomes of ketogenic diet therapy were satisfactory. Nineteen cases out of 20 cases had a significantly higher ratio of plasma BCAAs:ARAAs during ketogenic diets than before the diet (P < 0.001). CONCLUSION: The ketogenic diets produced an increased ratio of plasma BCAAs:ARAAs. Whether the increased ratio of plasma BCAAs:ARAAs plays an important role in controlling epilepsy is yet to be elucidated.

Copyright 2011 Steve Kriegler