title: ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice.
abstract: The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1(-/-) or Cnr2(-/-) mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.
authors.affiliation: Medical Scientist Training Program, University of Washington, Seattle Washington, 98195, USA.|Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Alipi V
authors.initials: AV
authors.lastname: Naydenov
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Horne
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Cheah
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Swinney
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, 92037, USA.
authors.forename: Ku-Lung
authors.initials: KL
authors.lastname: Hsu
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Cao
authors.affiliation: Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: William
authors.initials: W
authors.lastname: Marrs
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, 92037, USA.
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tu
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Allison E
authors.initials: AE
authors.lastname: Cherry
authors.affiliation: Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Fung
authors.affiliation: Department of Biology, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Wen
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, 92037, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.affiliation: Melior Discovery, Inc., Exton, Pennsylvania, 19341, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Saporito
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, 23298, USA.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, 92037, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.|Department of Neurology, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Oakley
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, 98195 USA.
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D010433:Pentylenetetrazole; D043882:Receptors, Cannabinoid / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D043882:Receptors, Cannabinoid; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases; D010433:Pentylenetetrazole