ZINGIBER OFFICINALE ROSCOE RHIZOME EXTRACT ALLEVIATES NEUROPATHIC PAIN IN MICE BY REDUCING NEUROINFLAMMATION THROUGH THE INHIBITION OF CLASS I HDAC ISOFORMS

Current therapies for neuropathic pain are generally symptomatic and possess several side effects, limiting their pro- longed usage. Thus, it is urgent to develop novel and safe candidates for the management of this chronic condition. For this purpose, we investigated the analgesic effect of a Zingiber officinale Roscoe extract (ZOE), standardized in gingerols and terpenes, in a mice model of peripheral neuropathy. We also explored the mechanism of action of ZOE and its main constituents using an in vitro model of neuroinflammation. HDAC has a pivotal role in the development of neuropathic pain, thus, we also investigated the ability of ZOE and its constituents to inhibit HDAC isoforms expression and activity. METHODS: Peripheral mono-neuropathy was induced in mice, by spared nerve injury (SNI). The analgesic effect of ZOE after oral administration was assessed by measuring mechanical and ther- mal allodynia in SNI mice. The mechanism of ac- tion of ZOE and its main constituents was inves- tigated using spinal cord samples and an in vitro model of neuroinflammation by ELISA, western blotting and immunofluorescence techniques. RESULTS: Oral administration of ZOE 200 mg kg-1 ameliorated mechanical and thermal allo- dynia in SNI mice, with a rapid and a long-last- ing effect without altering locomotor activity. In BV2 cells and spinal cord samples, ZOE modu- lated MAPKs activation and HDAC expression. The activity on HDAC was found to be selective for class I isoforms and mainly mediated by the terpenes fraction. The anti-inflammatory effect of ZOE and its constituents led to a neuroprotective effect on inflammation-impaired SH-SY5Y cell viability. CONCLUSIONS: The oral administration of ZOE attenuated SNI-induced neuropathic pain symp- toms by reducing spinal neuroinflammation, suggesting ZOE as a novel and interesting candidate for the management of neuropathic pain.