2014 Jul 16;83(2):361-371. 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.
Naydenov AV1, Horne EA2, Cheah CS2, Swinney K2, Hsu KL3, Cao JK2, Marrs WR4, Blankman JL3, Tu S2,Cherry AE2, Fung S4, Wen A5, Li W3, Saporito MS6, Selley DE7, Cravatt BF3, Oakley JC8, Stella N9.
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 atcannabinoid 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.
Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.
- PMID:
- 25033180
- [PubMed – as supplied by publisher]
