Re-examining the potential of targeting ABHD6 in multiple sclerosis: Efficacy of systemic and peripherally restricted inhibitors in experimental autoimmune encephalomyelitis

Manterola, Andrea; Bernal‐Chico, Ana; Cipriani, Raffaela; Ruiz, Asier; Pérez-Samartı́n, Alberto; Moreno‐Rodríguez, Marta; Hsu, Ku‐Lung; Cravatt, Benjamin F.; Brown, J. Mark; Rodrı́guez-Puertas, Rafael; Matute, Carlos; Mato, Susana

doi:10.1016/j.neuropharm.2018.08.038

Cited by 21 publications

(27 citation statements)

References 36 publications

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“…Recent studies suggest that ABHD6 inhibitor have promising therapeutic efficacy in several preclinical mouse models of devastating diseases (Cao et al, 2019), such as metabolic syndrome (Thomas et al, 2013), chronic inflammation (Alhouayek et al, 2013), diabetes (Zhao et al, 2014), including traumatic brain injury (Tchantchou and Zhang, 2013), multiple sclerosis (Manterola et al, 2018), and epilepsy (Naydenov et al, 2014). Thus, it is important to further study the impact of the DAG lipase activity of ABHD6 on these pathophysiological processes to help develop novel therapeutics based on inhibiting ABHD6 activity.…”

Section: Discussionmentioning

confidence: 99%

Identification of α,β-Hydrolase Domain Containing Protein 6 as a Diacylglycerol Lipase in Neuro-2a Cells

Esbroeck

Kantae

et al. 2019

Front. Mol. Neurosci.

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The endocannabinoid 2-arachidonoylglycerol (2-AG) is involved in neuronal differentiation. This study aimed to identify the biosynthetic enzymes responsible for 2-AG production during retinoic acid (RA)-induced neurite outgrowth of Neuro-2a cells. First, we confirmed that RA stimulation of Neuro-2a cells increases 2-AG production and neurite outgrowth. The diacylglycerol lipase (DAGL) inhibitor DH376 blocked 2-AG production and reduced neuronal differentiation. Surprisingly, CRISPR/Cas9-mediated knockdown of DAGLα and DAGLβ in Neuro-2a cells did not reduce 2-AG levels, suggesting another enzyme capable of producing 2-AG in this cell line. Chemical proteomics revealed DAGLβ and α,β-hydrolase domain containing protein (ABHD6) as the only targets of DH376 in Neuro-2a cells. Biochemical, genetic and lipidomic studies demonstrated that ABHD6 possesses DAGL activity in conjunction with its previously reported monoacylglycerol lipase activity. RA treatment of Neuro-2a cells increased by three-fold the amount of active ABHD6. Our study shows that ABHD6 exhibits significant DAG lipase activity in Neuro-2a cells in addition to its known MAG lipase activity and suggest it is involved in neuronal differentiation.

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Section: Discussionmentioning

confidence: 99%

Identification of α,β-Hydrolase Domain Containing Protein 6 as a Diacylglycerol Lipase in Neuro-2a Cells

Esbroeck

Kantae

et al. 2019

Front. Mol. Neurosci.

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“…We identified 5 studies that evaluated the efficacy of the combination of Δ9-THC+CBD in decreasing clinical symptoms of EAE [ 61 , 62 , 63 , 64 , 65 ]; 6 studies that evaluated the efficacy of CB2R agonists in decreasing clinical symptoms of EAE [ 66 , 67 , 68 , 69 , 70 , 71 ]; 2 studies that evaluated the efficacy of exogenous administration of endocannabinoids or endocannabinoids-derivatives in MS [ 72 , 73 ]; 1 study that evaluated the efficacy of CB1R agonists in decreasing clinical symptoms of EAE [ 74 ]; 10 studies that evaluated the efficacy of CB1R, CB2R agonists in decreasing clinical symptoms of EAE [ 62 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ] and 5 studies that evaluated the protective effect of increasing the endocannabinoid levels in EAE animal models by inhibiting the enzymes that metabolize the endocannabinoids as ABHD6 [ 84 , 85 ] and MAGL [ 86 , 87 , 88 ].…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of ABHD6 enzyme that leads to increase of 2-AG in the CNS can have promising results in the treatment of MS. KT182 compound, an inhibitor of ABHD6, succeeded in decreasing the motor disability but failed to induce neuro-anti-inflammatory effects [ 84 ]. On the other side, WWL70 compound, another inhibitor of ABHD6, proved more promising results by increasing 2-AG levels and improving clinical manifestation of MS, mainly by increasing 2-AG levels in microglia/macrophage and acting on CB2R, leading to decreased microglia activation and decreased production of inflammatory markers and adhesion molecules [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation—Evidence from In Vivo Studies

Calina

Buga

Mitroi

et al. 2020

JCM

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Neurological disorders such as neurodegenerative diseases or traumatic brain injury are associated with cognitive, motor and behavioural changes that influence the quality of life of the patients. Although different therapeutic strategies have been developed and tried until now to decrease the neurological decline, no treatment has been found to cure these pathologies. In the last decades, the implication of the endocannabinoid system in the neurological function has been extensively studied, and the cannabinoids have been tried as a new promising potential treatment. In this study, we aimed to overview the recent available literature regarding in vivo potential of natural and synthetic cannabinoids with underlying mechanisms of action for protecting against cognitive decline and motor impairments. The results of studies on animal models showed that cannabinoids in traumatic brain injury increase neurobehavioral function, working memory performance, and decrease the neurological deficit and ameliorate motor deficit through down-regulation of pro-inflammatory markers, oedema formation and blood–brain barrier permeability, preventing neuronal cell loss and up-regulating the levels of adherence junction proteins. In neurodegenerative diseases, the cannabinoids showed beneficial effects in decreasing the motor disability and disease progression by a complex mechanism targeting more signalling pathways further than classical receptors of the endocannabinoid system. In light of these results, the use of cannabinoids could be beneficial in traumatic brain injuries and multiple sclerosis treatment, especially in those patients who display resistance to conventional treatment.

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“…Although inhibitors of the ABHD6 enzyme produced a similar reduction in intracellular and extracellular brevican despite hydrolyzing only 3% of the 2‐AG, the therapeutic effect of ABHD6 inhibitors in vivo remains controversial. While there is evidence that inhibiting ABDH6 produces therapeutic effects in a CNS injury model (Tchantchou & Zhang, ) or in the EAE model of MS (Wen, Ribeiro, Tanaka, & Zhang, ), only modest effects were observed when ABHD6 was inhibited by KT182 in the cuprizone model of demyelination and in EAE (Manterola et al, ; Manterola et al, ). Our observations strongly suggest that 2‐AG dampens the production of neurocan and brevican in TGF‐β1 stimulated astrocytes by modulating SMAD signaling.…”

Section: Discussionmentioning

confidence: 99%

2‐arachidonoylglycerol reduces chondroitin sulphate proteoglycan production by astrocytes and enhances oligodendrocyte differentiation under inhibitory conditions

Feliú

Mestre

Carrillo‐Salinas

et al. 2020

Glia

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The failure to remyelinate and regenerate is a critical impediment to recovery in multiple sclerosis (MS), resulting in severe dysfunction and disability. The chondroitin sulfate proteoglycans (CSPGs) that accumulate in MS lesions are thought to be linked to the failure to regenerate, impeding oligodendrocyte precursor cell (OPC) differentiation and neuronal growth. The potential of endocannabinoids to influence MS progression may reflect their capacity to enhance repair processes. Here, we investigated how 2‐arachidonoylglycerol (2‐AG) may affect the production of the CSPGs neurocan and brevican by astrocytes in culture. In addition, we studied whether 2‐AG promotes oligodendrocyte differentiation under inhibitory conditions in vitro. Following treatment with 2‐AG or by enhancing its endogenous tone through the use of inhibitors of its hydrolytic enzymes, CSPG production by rat and human TGF‐β1 stimulated astrocytes was reduced. These effects of 2‐AG might reflect its influence on TGF‐β1/SMAD pathway, signaling that is involved in CSPG upregulation. The matrix generated from 2‐AG‐treated astrocytes is less inhibitory to oligodendrocyte differentiation and significantly, 2‐AG administration directly promotes the differentiation of rat and human oligodendrocytes cultured under inhibitory conditions. Overall, the data obtained favor targeting the endocannabinoid system to neutralize CSPG accumulation and to enhance oligodendrocyte differentiation.

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Re-examining the potential of targeting ABHD6 in multiple sclerosis: Efficacy of systemic and peripherally restricted inhibitors in experimental autoimmune encephalomyelitis

Cited by 21 publications

References 36 publications

Identification of α,β-Hydrolase Domain Containing Protein 6 as a Diacylglycerol Lipase in Neuro-2a Cells

Identification of α,β-Hydrolase Domain Containing Protein 6 as a Diacylglycerol Lipase in Neuro-2a Cells

The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation—Evidence from In Vivo Studies

2‐arachidonoylglycerol reduces chondroitin sulphate proteoglycan production by astrocytes and enhances oligodendrocyte differentiation under inhibitory conditions

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