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Epilepsia. 2018 Jan;59(1):79-91. doi: 10.1111/epi.13950. Epub 2017 Nov 24.

Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet.

Author information

1
Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy.
2
Department of Oncology, IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy.
3
Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
4
Medicinal Chemistry, Pfizer Worldwide Research & Development, Cambridge, MA, USA.

Abstract

OBJECTIVE:

Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures. We studied the effect of a potent and selective irreversible MAGL inhibitor, CPD-4645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug's effects.

METHODS:

Diazepam-resistant SE was induced in adult mice fed with standard or ketogenic diet or in cannabinoid receptor type 1 (CB1) receptor knock-out mice. CPD-4645 (10 mg/kg, subcutaneously) or vehicle was dosed 1 and 7 h after status epilepticus onset in video-electroencephalography (EEG) recorded mice. At the end of SE, mice were examined in the novel object recognition test followed by neuronal cellloss analysis.

RESULTS:

CPD-4645 maximal plasma and brain concentrations were attained 0.5 h postinjection (half-life = 3.7 h) and elevated brain 2-AG levels by approximately 4-fold. CPD-4645 administered to standard diet-fed mice progressively reduced spike frequency during 3 h postinjection, thereby shortening SE duration by 47%. The drug immediately abrogated SE in ketogenic diet-fed mice. CPD-4645 rescued neuronal cell loss and cognitive deficit and reduced interleukin (IL)-1β and cyclooxygenase 2 (COX-2) brain expression resulting from SE. The CPD-4645 effect on SE was similar in mice lacking CB1 receptors.

SIGNIFICANCE:

MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD-4645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation.

KEYWORDS:

2-arachidonoylglycerol; arachidonic acid; cognitive deficits; de novo refractory status epilepticus; endocannabinoid; ketogenic diet; monoacylglycerol lipase; neuroinflammation

PMID:
29171003
DOI:
10.1111/epi.13950
[Indexed for MEDLINE]
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