Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury.

Chen Dai,Baogan Peng,Jiezhi Lin,Bin Liu,Bo Qu,Bibo Peng,Duan-Ming Li

doi:10.3389/fphar.2021.774539

Abstract

Background: Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. We tried to uncover the potential neuroprotective role of entinostat (a class I HDAC inhibitor) in SCI. Methods: We conducted a study on a preclinical mouse model of SCI and OGD-induced neuronal damage to present the role of entinostat by the analysis of motor function, histopathologic damage, local NLRP3 inflammasome activation, and neuronal damage. Results: The results showed that entinostat suppressed HDAC activation (including HDAC1 and HDAC3 expression), improved the grip strength and BMS score, spinal edema, cell death, and local NLRP3 inflammasome activation in the spinal cord following SCI. Furthermore, entinostat significantly increased OGD-inhibited neuronal activity and decreased PI-positive cells, HDAC activation, caspase-1 activation, IL-1β and IL-18 levels, and NLRP3 expression. Conclusion: In summary, we first documented that entinostat improved the motor function, histopathologic damage, and local inflammatory response and NLRP3 inflammasome activation in the spinal cord following SCI and also presented the neuroprotective role of OGD-induced neuronal damage via the NLRP3 inflammasome. Thus, our study has the potential to reveal the interaction between the HDAC and NLRP3 inflammasome in the pathologic process as well as SCI and further promote the clinical indications of HDACi entinostat and clinical treatment for the inflammatory response after SCI.

Highlights

Spinal cord injury (SCI), a major public health problem, has no effective treatment
The data showed that high concentrations of entinostat (5 mg/kg and 10 mg/kg) treatment presented the protection of motor function following SCI
Zhang et al showed that the variation trend of histone deacetylases (HDACs) in the spinal cord of the SCI model is inconsistent with previous reports, they revealed that the inhibition of both HDAC1 and HDAC 3 of CI-994 may exert a neuroprotective effect (Zhang S. et al, 2018)

Summary

Introduction

Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. With a high global incidence rate (10.4–83 per million people per year), spinal cord injury (SCI) results in severe long-term disability as it deprives many patients of motor function (Karsy and Hawryluk, 2019), induced by motor vehicle accidents, violence, falls, and recreational activities. Previous research studies have confirmed that damaged cells, axons, and blood vessels release toxic chemicals that attack intact neighboring cells after SCI, and the secondary events include excitotoxicity and inflammation (McDonald and Sadowsky, 2002; Fouad et al, 2021). Chen et al have demonstrated that AZD8797, an inhibitor of CX3CR1, effectively blocks overwhelming inflammation, apoptosis, and necrosis after SCI and facilitates early recovery of locomotive function (Chen et al, 2020)

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