Compounds that target endocannabinoid (eCB) signaling in the brain represent powerful pharmacological tools to probe the basic biological function of this signaling system in healthy and diseased brain and may represent novel therapeutic venues to treat neurological diseases such as Huntington's disease (HD). During the funding cycle of this RO1, our laboratory studied the function of ABHD6 in neurons and glia, as well as the therapeutic potential of ABHD6 inhibitors in R6/2 mice, an early-onset mouse model of HD. We leveraged functional proteomics and shRNA technology and identified ABHD6 as a candidate enzyme for 2-AG hydrolysis in brain. We then developed new ABHD6 inhibitors and showed that ABHD6 activity tightly controls the levels and efficacy of 2-AG at cannabinoid receptors. Together, these studies demonstrated that ABHD6 belongs to the eCB signaling system. Recently we found that in vivo ABHD6 inhibition greatly reduces seizure incidence and attenuates hippocampal neuropathology in R6/2 mice. In this grant, we will test the following hypothesis: The novel enzyme, ABHD6, controls both the level and efficacy of 2-arachidonoylglycerol (2-AG) at cannabinoid CB1 receptors. ABHD6 inhibitors reduce seizure activity in two HD mouse models (R6/2 and HDQ200) and may represent a novel class of therapeutics to treat seizures in general. To test this hypothesis, we propose 3 Aims:
AIM 1 : Development, validation, and mechanism of action of 3rd generation ABHD6 inhibitors that exhibit superior in vivo selectivity and efficacy.
AIM 2 : Determine to what extent ABHD6 in vivo inhibition and genetic deletion reduces seizure incidence in HD and chemically-induced seizures mouse models.
AIM 3 : Why do HD mice seize, and how does ABHD6 prevent this process? Thus we will characterize newly optimized inhibitors of ABHD6, an eCB-hydrolyzing enzyme that we identified during the previous funding period. Coupled to genetic approaches, we will use ABHD6 inhibitors to determine the molecular and cellular details of how this enzyme controls seizure incidence in HD mice models. Completion of the studies outlined above will provide a comprehensive understanding of the role of ABHD6 in healthy and HD mouse brain within the context of epileptic activity. Our long-term goal is to increase our understanding of th role played by ABHD6 in healthy and diseased brain, and help develop novel therapeutics that lack the potential for abuse and adverse effects produced by classic cannabinoid agonists.

Public Health Relevance

Compounds that target the endocannabinoid (eCB) signaling in brain represent powerful tools to discover the basic biological function of this signaling syste and represent promising therapeutics to treat neurological diseases such as Huntington's disease (HD). Here we will use newly optimized inhibitors of the eCB hydrolyzing enzyme, ABHD6, in combination with genetics to determine how this enzyme controls seizure incidence in HD and chemically-induced seizures mouse models. This research will provide a comprehensive understanding of the expression, activity and role of ABHD6 in healthy and HD brain within the context of epileptic activity, with the potential of developing novel therapeutics that will benefit patients with HD while avoiding the abuse liability and adverse effects produced by cannabinoid agonists.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DA026430-06
Application #
8628656
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Di Marzo, Vincenzo; Stella, Nephi; Zimmer, Andreas (2015) Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 16:30-42
Naydenov, Alipi V; Sepers, Marja D; Swinney, Katie et al. (2014) Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in HD mice. Neurobiol Dis 71:140-50
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Kow, Rebecca L; Jiang, Kelly; Naydenov, Alipi V et al. (2014) Modulation of pilocarpine-induced seizures by cannabinoid receptor 1. PLoS One 9:e95922
Naydenov, Alipi V; Horne, Eric A; Cheah, Christine S et al. (2014) ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice. Neuron 83:361-71
Horne, Eric A; Coy, Jonathan; Swinney, Katie et al. (2013) Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington's disease and mouse models. Eur J Neurosci 37:429-40
Stella, Nephi (2013) Chronic THC intake modifies fundamental cerebellar functions. J Clin Invest 123:3208-10
Chen, Dong-Hui; Naydenov, Alipi; Blankman, Jacqueline L et al. (2013) Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects. Hum Mutat 34:1672-8
Kwan, Wanda; Träger, Ulrike; Davalos, Dimitrios et al. (2012) Mutant huntingtin impairs immune cell migration in Huntington disease. J Clin Invest 122:4737-47

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