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.
journal_name
Neuronjournal_title
Neuronauthors
Naydenov AV,Horne EA,Cheah CS,Swinney K,Hsu KL,Cao JK,Marrs W,Blankman JL,Tu S,Cherry AE,Fung S,Wen A,Li W,Saporito MS,Selley DE,Cravatt BF,Oakley JC,Stella Ndoi
10.1016/j.neuron.2014.06.030subject
Has Abstractpub_date
2014-07-16 00:00:00pages
361-371issue
2eissn
0896-6273issn
1097-4199journal_volume
83pub_type
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