HDAC6 inhibitor ACY-1215 improves neuropathic pain and its comorbidities in rats of peripheral nerve injury by regulating neuroinflammation

Abstract

The fact that neuropathic pain (NP) has no effective therapy and is frequently accompanied by psychiatric comorbidities is well established. Aberrant neuroinflammation plays an important role in the development and maintenance of NP. HDAC6 inhibitors have been demonstrated to ameliorate mechanical allodynia brought on by chemotherapy and peripheral nerve damage. However, its pharmacological mechanisms and its effects on NP-related mental disorders have not been fully elucidated. The present study was dedicated to exploring the effects of ACY-1215 (a specific HDAC6 inhibitor) on neuroinflammation and behavioral abnormalities associated with NP. In this work, spinal nerve ligation (SNL) was performed as an NP model on rats. Mechanical allodynia, cognitive impairment, and depressive-like behavior caused by SNL were attenuated by continuous intraperitoneal injection of ACY-1215. Moreover, ACY-1215 administration suppressed SNL-induced neuroinflammatory responses (including microgliosis, the elevation of pro-inflammatory factors IL-1β and TNF-α) in ligation of the ipsilateral spinal dorsal horn (iSDH), hippocampus (HPC) and prefrontal cortex (PFC). Mechanistically, MyD88-dependent pro-inflammatory pathways (MyD88/NF-κB and MyD88/ERK) were activated in the iSDH following SNL and were inhibited by ACY-1215. Moreover, ACY-1215 enhanced the acetylation modification of MyD88 and inhibited the SNL-induced elevation of MyD88 without affecting its transcription in the iSDH. These findings suggest that pharmacological inhibition of HDAC6 can ameliorate NP and its psychiatric complications through modulating neuroinflammation, in part by blocking the MyD88-mediated pro-inflammatory pathways. The possible mechanism is that ACY-1215 prevents the elevation of MyD88 reactivity by increasing its acetylation level. Notably, neither SNL nor ACY-1215 significantly altered MyD88 expression in HPC and PFC, indicating differentiated pro-inflammatory mechanisms in the supraspinal neural regions.

Keywords: HDAC6; MyD88; Neuroinflammation; Neuropathic pain.