title: Potent anti-seizure effects of D-leucine.
abstract: There are no effective treatments for millions of patients with intractable epilepsy. High-fat ketogenic diets may provide significant clinical benefit but are challenging to implement. Low carbohydrate levels appear to be essential for the ketogenic diet to work, but the active ingredients in dietary interventions remain elusive, and a role for ketogenesis has been challenged. A potential antiseizure role of dietary protein or of individual amino acids in the ketogenic diet is understudied. We investigated the two exclusively ketogenic amino acids, L-leucine and L-lysine, and found that only L-leucine potently protects mice when administered prior to the onset of seizures induced by kainic acid injection, but not by inducing ketosis. Unexpectedly, the D-enantiomer of leucine, which is found in trace amounts in the brain, worked as well or better than L-leucine against both kainic acid and 6Hz electroshock-induced seizures. However, unlike L-leucine, D-leucine potently terminated seizures even after the onset of seizure activity. Furthermore, D-leucine, but not L-leucine, reduced long-term potentiation but had no effect on basal synaptic transmission in vitro. In a screen of candidate neuronal receptors, D-leucine failed to compete for binding by cognate ligands, potentially suggesting a novel target. Even at low doses, D-leucine suppressed ongoing seizures at least as effectively as diazepam but without sedative effects. These studies raise the possibility that D-leucine may represent a new class of anti-seizure agents, and that D-leucine may have a previously unknown function in eukaryotes.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. Electronic address: ahartma2@jhmi.edu.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Hartman
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Polan
authors.initials: P
authors.lastname: Santos
authors.affiliation: Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Riordan
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Stafstrom
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. Electronic address: hardwick@jhu.edu.
authors.forename: J
authors.initials: J
authors.lastname: Marie Hardwick
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D007608:Kainic Acid; D007930:Leucine / Q000494:pharmacology / Q000627:therapeutic use*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D009435:Synaptic Transmission / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D007930:Leucine; D007608:Kainic Acid
keywords: Amino acids; Epilepsy; Kainic acid; Preclinical testing