ABHD6 Blockade Exerts Antiepileptic Activity in PTZ-Induced Seizures and in Spontaneous Seizures in R6/2 Mice

Naydenov, Alipi V.; Horne, Eric A.; Cheah, Christine S.; Swinney, Katie; Hsu, Ku‐Lung; Cao, Jessica K.; Marrs, William R.; Blankman, Jacqueline L.; Tu, Sarah; Cherry, Allison E.; Fung, Susan; Wen, Andy; Li, Weiwei; Saporito, Michael S.; Selley, Dana E.; Cravatt, Benjamin F.; Oakley, John C.; Stella, Nephi

doi:10.1016/j.neuron.2014.06.030

Cited by 100 publications

(112 citation statements)

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“…Therefore, the reduced production of the inflammatory prostaglandins by inhibition of ABHD6 may also contribute to the therapeutic effect of WWL70 in the EAE mouse model. Interestingly, a recent study has shown that inhibition of ABHD6 protects against pentylenetetrazole-induced seizure in C57BL/6 mice via activation of GABA A receptors, rather than activation of cannabinoid receptors (Naydenov et al, 2014). This finding is consistent with the report that 2-AG can directly activate GABA A receptor (Sigel et al, 2011), and therefore is able to maintain the balance between the inhibitory and excitatory neurotransmitters and prevent glutamate induced excitotoxicity.…”

Section: Discussionsupporting

confidence: 87%

“…Inhibition of ABHD6 has been suggested to fine-tune the 2-AG signaling in brain and shown to be effective in the animal models of traumatic brain injury and epileptic seizure (Marrs et al, 2010;Naydenov et al, 2014;Tchantchou and Zhang, 2013). Very recently, enhancement of 2-AG signaling by inhibition of its major hydrolytic enzyme MAGL is also shown to attenuate neuroinflammation and neurodegeneration in the mouse model of mild traumatic brain injury (Katz et al, 2015;Zhang et al, 2015).…”

Section: Inhibition Of Abhd6 Ameliorated Clinical Signs Of Eaementioning

confidence: 99%

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Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

et al. 2015

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Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system. Recently we and others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Post-symptom treatment with an ABHD6 inhibitor WWL70 increased the brain levels of 2-AG and ameliorated the clinical signs of EAE, T cells infiltration, microglia activation and the expression of activated leukocyte cell adhesion molecules. The production of iNOS, COX-2, TNF-α and IL-1β and the phosphorylation of NF-κB were also significantly reduced by WWL70 treatment. The neuroprotective effect of WWL70 was demonstrated by increased survival of mature oligodendrocytes, reduced demyelination and axonal loss in WWL70 treated EAE mouse spinal cord. The therapeutic effect of WWL70 on EAE was absent by co-administration of CB2 receptor antagonist, but not CB1 receptor antagonist. Consistently, WWL70 did not afford any protection in CB2 receptor knockout mice after EAE induction. Given the increased expression of ABHD6 in microglia/macrophages, but not in T cells, we speculated that inhibition of ABHD6 might enhance 2-AG signaling particularly in microglia/macrophages to exert anti-inflammatory effects via activation of CB2 receptors. These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 87%

Section: Inhibition Of Abhd6 Ameliorated Clinical Signs Of Eaementioning

confidence: 99%

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

et al. 2015

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“…14,27 These effects were attributed to a reduction of excitatory neurotransmission by 2-AG activation of CB1 receptors. MAGL inhibition may mediate therapeutic effects on SE by 2 main mechanisms: (1) accumulation of 2-AG, which in turn activates the neuronal presynaptic CB1 receptors, thereby reducing glutamate-mediated excitatory over inhibitory neurotransmission 28,29 or acting as allosteric modulator of c-aminobutyric acid A (GABA A ) receptors 30 ;…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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SummaryObjective: 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)-1b and cyclooxygenase 2 (COX-2) brain expression resulting from SE. The CPD-4645 effect on SE was similar in mice lacking CB1 receptors.Gaetano Terrone, Alberto Pauletti, and Alessia Salamone share first authorship. Gaetano Terrone is on leave

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“…Chronic WWL70 treatment after traumatic brain injury exerted a neuroprotective effect by increasing the levels of 2-AG in the brain (47). Pretreating mice with WWL123, another brain-penetrant ABHD6 inhibitor, alleviated epileptic symptoms during pentylenetetrazole-induced seizures, and this blockade was absent in the presence of γ-aminobutyric acid type A receptor antagonists (48).…”

mentioning

confidence: 98%

α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

Wei

Zhang

Jia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.ABHD6 | AMPA receptor | synapses | receptor trafficking

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ABHD6 Blockade Exerts Antiepileptic Activity in PTZ-Induced Seizures and in Spontaneous Seizures in R6/2 Mice

Cited by 100 publications

References 65 publications

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

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

α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

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