Potent anti-seizure effects of D-leucine

Hartman, Adam L.; Santos, Polan T.; O’Riordan, Kenneth J.; Stafstrom, Carl E.; Hardwick, J. Marie

doi:10.1016/j.nbd.2015.05.013

Cited by 43 publications

(38 citation statements)

References 64 publications

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“…Leucine also results in hepatic ketogenesis ( Holecek et al, 2003 ). Studies in mice have shown that while ingested L-leucine can reduce seizure activity similarly to a KD, it does not independently increase blood levels of BOHB ( Hartman et al, 2015 ). Evangeliou and colleagues have demonstrated that the addition of 20 g per day of BCAAs, including 9 g of leucine, in 17 children with intractable epilepsy, altering the ratio of lipid to protein from 4:1 to around 2.5:, had no effect on ketosis, along with greater reductions in seizure activity.…”

Section: Resultsmentioning

confidence: 99%

The use of nutritional supplements to induce ketosis and reduce symptoms associated with keto-induction: a narrative review

Harvey

Schofield

Williden

2018

PeerJ

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BackgroundAdaptation to a ketogenic diet (keto-induction) can cause unpleasant symptoms, and this can reduce tolerability of the diet. Several methods have been suggested as useful for encouraging entry into nutritional ketosis (NK) and reducing symptoms of keto-induction. This paper reviews the scientific literature on the effects of these methods on time-to-NK and on symptoms during the keto-induction phase.MethodsPubMed, Science Direct, CINAHL, MEDLINE, Alt Health Watch, Food Science Source and EBSCO Psychology and Behavioural Sciences Collection electronic databases were searched online. Various purported ketogenic supplements were searched along with the terms “ketogenic diet”, “ketogenic”, “ketosis” and ketonaemia (/ ketonemia). Additionally, author names and reference lists were used for further search of the selected papers for related references.ResultsEvidence, from one mouse study, suggests that leucine doesn’t significantly increase beta-hydroxybutyrate (BOHB) but the addition of leucine to a ketogenic diet in humans, while increasing the protein-to-fat ratio of the diet, doesn’t reduce ketosis. Animal studies indicate that the short chain fatty acids acetic acid and butyric acid, increase ketone body concentrations. However, only one study has been performed in humans. This demonstrated that butyric acid is more ketogenic than either leucine or an 8-chain monoglyceride. Medium-chain triglycerides (MCTs) increase BOHB in a linear, dose-dependent manner, and promote both ketonaemia and ketogenesis. Exogenous ketones promote ketonaemia but may inhibit ketogenesis.ConclusionsThere is a clear ketogenic effect of supplemental MCTs; however, it is unclear whether they independently improve time to NK and reduce symptoms of keto-induction. There is limited research on the potential for other supplements to improve time to NK and reduce symptoms of keto-induction. Few studies have specifically evaluated symptoms and adverse effects of a ketogenic diet during the induction phase. Those that have typically were not designed to evaluate these variables as primary outcomes, and thus, more research is required to elucidate the role that supplementation might play in encouraging ketogenesis, improve time to NK, and reduce symptoms associated with keto-induction.

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Section: Resultsmentioning

confidence: 99%

The use of nutritional supplements to induce ketosis and reduce symptoms associated with keto-induction: a narrative review

Harvey

Schofield

Williden

2018

PeerJ

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“…24 Recently, D-leucine has been applied as an effective treatment for seizures in mice. 25 However, the exact mechanism through which D-leucine acts to inhibit seizure activity remains unknown. D-Serine and D-leucine are two recent and prominent examples of D-amino acids found in brain tissues having specific function or actions.…”

Section: Introductionmentioning

confidence: 99%

d-Amino Acid Levels in Perfused Mouse Brain Tissue and Blood: A Comparative Study

Weatherly

Parpia

et al. 2017

ACS Chem. Neurosci.

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103

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The L-enantiomer is the predominant type of amino acid in all living systems. However, D-amino acids, once thought to be “unnatural”, have been found to be indigenous even in mammalian systems and increasingly appear to be functioning in essential biological and neurological roles. Both D- and L-amino acid levels in the hippocampus, cortex, and blood samples from NIH Swiss mice are reported. Perfused brain tissues were analyzed for the first time, thereby eliminating artifacts due to endogenous blood, and decreased the mouse-to-mouse variability in amino acid levels. Total amino acid levels (L-plus D-enantiomers) in brain tissue are up to 10 times higher than in blood. However, all measured D-amino acid levels in brain tissue are typically ~10 to 2000 times higher than blood levels. There was a 13% reduction in almost all measured D-amino acid levels in the cortex compared to those in the hippocampus. There is an approximate inverse relationship between the prevalence of an amino acid and the percentage of its D-enantiomeric form. Interestingly, glutamic acid, unlike all other amino acids, had no quantifiable level of its D-antipode. The bioneurological reason for the unique and conspicuous absence/removal of this D-amino acid is yet unknown. However, results suggest that D-glutamate metabolism is likely a unidirectional process and not a cycle, as per the L-glutamate/glutamine cycle. The results suggest that there might be unreported D-amino acid racemases in mammalian brains. The regulation and function of specific other D-amino acids are discussed.

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“…Dleucine has potential anti-seizure properties. [17]. In the present study we evaluated the combinatorial effect of D-AAs with antibiotics.…”

Section: Methodsmentioning

confidence: 99%

Combinatorial Effect of D-Aminoacids and Tetracycline Against Pseudomonas Aeruginosa Biofilm

Jayalekshmi

Harikrishnan

Sali

et al. 2016

Int J Pharm Pharm Sci

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Objective: The present study attempted to evaluate the anti-biofilm activity of D-amino acids (D-AAs) on Pseudomonas aeruginosa and determine if the combination of D-AAs with tetracycline enhances the anti-biofilm activity in vitro and ex vivo. Methods:Different D-AAs were tested for antibiofilm activity against wild type P. aeruginosa PAO1 and two multidrug resistant P. aeruginosa clinical strains in the presence of sub inhibitory concentrations of tetracycline using crystal violet microtitre plate assay. Results were further validated using in vitro wound dressing and ex vivo porcine skin models followed by cytotoxicity and hemocompatibility studies.Results: D-tryptophan (5 mmol) showed 61 % reduction in biofilm formation of P. aeruginosa. Interestingly combinatorial effect of 5 mmol Dtryptophan and 0.5 minimum inhibitory concentration (MIC) (7.5µg/ml) tetracycline showed 90% reduction in biofilm formation. 5 mmol Dmethionine shows 28 % reduction and combination with tetracycline shows 41% reduction in biofilm formation of P. aeruginosa. D-leucine and Dtyrosine alone or in combination with tetracycline did not show significant anti-biofilm activity. D tryptophan-tetracycline combination could reduce 80 % and 77 % reduction in biofilm formation in two multi drug resistant P. aeruginosa clinical strains. D-tryptophan-tetracyclinecombination could also reduce 76% and 66% reduction in biofilm formation in wound dressing model and porcine skin explant respectively. The cytotoxicity and hemocompatibility studies did not show significant toxicity when this combination was used. Conclusion:The results established the potential therapeutic application of D-tryptophan alone or in combination with tetracycline for treating biofilm associated clinical problems caused by P. aeruginosa.

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Potent anti-seizure effects of D-leucine

Cited by 43 publications

References 64 publications

The use of nutritional supplements to induce ketosis and reduce symptoms associated with keto-induction: a narrative review

The use of nutritional supplements to induce ketosis and reduce symptoms associated with keto-induction: a narrative review

d-Amino Acid Levels in Perfused Mouse Brain Tissue and Blood: A Comparative Study

Combinatorial Effect of D-Aminoacids and Tetracycline Against Pseudomonas Aeruginosa Biofilm

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