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

Gaetano Terrone, Alberto Pauletti, Alessia Salamone, Massimo Rizzi, Bianca R Villa, Luca Porcu, Mark J Sheehan, Edward Guilmette, Christopher R Butler, Justin R Piro, Tarek A Samad, Annamaria Vezzani

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)79-91
Number of pages13
JournalEpilepsia
Volume59
Issue number1
DOIs
Publication statusPublished - Jan 2018

Fingerprint

Monoacylglycerol Lipases
Ketogenic Diet
Status Epilepticus
Diazepam
Cannabinoid Receptor CB1
Brain
Seizures
Pharmaceutical Preparations
Endocannabinoids
Therapeutic Uses
Cyclooxygenase 2
Interleukin-1
Arachidonic Acid
Knockout Mice
Interleukin-2
Half-Life
Electroencephalography
Hydrolysis

Keywords

  • Animals
  • Brain/metabolism
  • Brain Waves/drug effects
  • Carbamates/chemistry
  • Cognition Disorders/drug therapy
  • Diazepam/adverse effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Resistant Epilepsy/chemically induced
  • Electroencephalography
  • Excitatory Amino Acid Agonists/toxicity
  • Fluoresceins/metabolism
  • Kainic Acid/toxicity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monoacylglycerol Lipases/antagonists & inhibitors
  • Neurons/drug effects
  • Piperidines/chemistry
  • Random Allocation
  • Receptor, Cannabinoid, CB1/deficiency
  • Recognition (Psychology)/drug effects
  • Status Epilepticus/chemically induced
  • Sulfonamides/chemistry
  • Time Factors

Cite this

Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet. / Terrone, Gaetano; Pauletti, Alberto; Salamone, Alessia; Rizzi, Massimo; Villa, Bianca R; Porcu, Luca; Sheehan, Mark J; Guilmette, Edward; Butler, Christopher R; Piro, Justin R; Samad, Tarek A; Vezzani, Annamaria.

In: Epilepsia, Vol. 59, No. 1, 01.2018, p. 79-91.

Research output: Contribution to journalArticle

Terrone, G, Pauletti, A, Salamone, A, Rizzi, M, Villa, BR, Porcu, L, Sheehan, MJ, Guilmette, E, Butler, CR, Piro, JR, Samad, TA & Vezzani, A 2018, 'Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet', Epilepsia, vol. 59, no. 1, pp. 79-91. https://doi.org/10.1111/epi.13950
Terrone, Gaetano ; Pauletti, Alberto ; Salamone, Alessia ; Rizzi, Massimo ; Villa, Bianca R ; Porcu, Luca ; Sheehan, Mark J ; Guilmette, Edward ; Butler, Christopher R ; Piro, Justin R ; Samad, Tarek A ; Vezzani, Annamaria. / Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet. In: Epilepsia. 2018 ; Vol. 59, No. 1. pp. 79-91.
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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.",
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author = "Gaetano Terrone and Alberto Pauletti and Alessia Salamone and Massimo Rizzi and Villa, {Bianca R} and Luca Porcu and Sheehan, {Mark J} and Edward Guilmette and Butler, {Christopher R} and Piro, {Justin R} and Samad, {Tarek A} and Annamaria Vezzani",
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TY - JOUR

T1 - Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet

AU - Terrone, Gaetano

AU - Pauletti, Alberto

AU - Salamone, Alessia

AU - Rizzi, Massimo

AU - Villa, Bianca R

AU - Porcu, Luca

AU - Sheehan, Mark J

AU - Guilmette, Edward

AU - Butler, Christopher R

AU - Piro, Justin R

AU - Samad, Tarek A

AU - Vezzani, Annamaria

N1 - Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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.

KW - Animals

KW - Brain/metabolism

KW - Brain Waves/drug effects

KW - Carbamates/chemistry

KW - Cognition Disorders/drug therapy

KW - Diazepam/adverse effects

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Drug Resistant Epilepsy/chemically induced

KW - Electroencephalography

KW - Excitatory Amino Acid Agonists/toxicity

KW - Fluoresceins/metabolism

KW - Kainic Acid/toxicity

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Monoacylglycerol Lipases/antagonists & inhibitors

KW - Neurons/drug effects

KW - Piperidines/chemistry

KW - Random Allocation

KW - Receptor, Cannabinoid, CB1/deficiency

KW - Recognition (Psychology)/drug effects

KW - Status Epilepticus/chemically induced

KW - Sulfonamides/chemistry

KW - Time Factors

U2 - 10.1111/epi.13950

DO - 10.1111/epi.13950

M3 - Article

VL - 59

SP - 79

EP - 91

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 1

ER -