ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice

Alipi V Naydenov; Eric A Horne; Christine S Cheah; Katie Swinney; Ku-Lung Hsu; Jessica K Cao; William Marrs; Jacqueline L Blankman; Sarah Tu; Allison E Cherry; Susan Fung; Andy Wen; Weiwei Li; Michael S Saporito; Dana E Selley; Benjamin F Cravatt; John C Oakley; Nephi Stella

doi:10.1016/j.neuron.2014.06.030

ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice

Neuron. 2014 Jul 16;83(2):361-371. doi: 10.1016/j.neuron.2014.06.030.

Authors

Alipi V Naydenov^#^{1

2}, Eric A Horne^#³, Christine S Cheah³, Katie Swinney³, Ku-Lung Hsu⁴, Jessica K Cao³, William Marrs², Jacqueline L Blankman⁴, Sarah Tu³, Allison E Cherry³, Susan Fung², Andy Wen⁵, Weiwei Li⁴, Michael S Saporito⁶, Dana E Selley⁷, Benjamin F Cravatt⁴, John C Oakley^{3

8}, Nephi Stella^{3

9}

Affiliations

¹ Medical Scientist Training Program, University of Washington, Seattle Washington, 98195, USA.
² Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, 98195, USA.
³ Department of Pharmacology, University of Washington, Seattle, Washington, 98195, USA.
⁴ The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, 92037, USA.
⁵ Department of Biology, University of Washington, Seattle, Washington, 98195, USA.
⁶ Melior Discovery, Inc., Exton, Pennsylvania, 19341, USA.
⁷ Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, 23298, USA.
⁸ Department of Neurology, University of Washington, Seattle, Washington, 98195, USA.
⁹ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, 98195 USA.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anticonvulsants / pharmacology
Anticonvulsants / therapeutic use*
Behavior, Animal / drug effects
Brain / drug effects*
Brain / physiopathology
Carbamates / pharmacology
Carbamates / therapeutic use*
Male
Mice
Mice, Knockout
Monoacylglycerol Lipases / antagonists & inhibitors*
Pentylenetetrazole
Receptors, Cannabinoid / genetics
Seizures / chemically induced
Seizures / drug therapy*
Seizures / physiopathology

Substances

Anticonvulsants
Carbamates
Receptors, Cannabinoid
ABHD6 protein, mouse
Monoacylglycerol Lipases
Pentylenetetrazole

Abstract

Publication types

MeSH terms

Substances

Grants and funding