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 language | English |
|---|---|
| Pages (from-to) | 79-91 |
| Number of pages | 13 |
| Journal | Epilepsia |
| Volume | 59 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2018 |
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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 journal › Article
}
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
C2 - 29171003
VL - 59
SP - 79
EP - 91
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 1
ER -