Yumin Zhang
Uniformed Services University, USA
Title: Targeting the 2-AG hydrolytic enzyme ABHD6 in experimental autoimmune encephalomyelitis
Biography
Biography: Yumin Zhang
Abstract
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 a selective ABHD6 inhibitor WWL70 dramatically ameliorated the clinical signs of EAE, T cells infiltration, microglia activation and the expression of activated leukocyte cell adhesion molecules which implicates the increased monocyte adhesion and migration in EAE mouse spinal cord. 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 clearly demonstrated by increased mature oligodendrocytes, reduced demyelination and axonal loss in WWL70 treated EAE mouse spinal cord. Interestingly, the therapeutic effect of WWL70 on EAE was remarkably reversed by co-administration of CB2 receptor antagonist, but not CB1 receptor antagonist. Consistently, WWL70 did not have any protective effect 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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