HDAC8 Inhibition Reduces Lesional Iba-1+ Cell Infiltration after Spinal Cord Injury without Effects on Functional Recovery

Abstract

Pan-histone deacetylase (HDAC) inhibition with valproic acid (VPA) has beneficial effects after spinal cord injury (SCI), although with side effects. We focused on specific HDAC8 inhibition, because it is known to reduce anti-inflammatory mediators produced by macrophages (Mφ). We hypothesized that HDAC8 inhibition improves functional recovery after SCI by reducing pro-inflammatory classically activated Mφ. Specific HDAC8 inhibition with PCI-34051 reduced the numbers of perilesional Mφ as measured by histological analyses, but did not improve functional recovery (Basso Mouse Scale). We could not reproduce the published improvement of functional recovery described in contusion SCI models using VPA in our T-cut hemisection SCI model. The presence of spared fibers might be the underlying reason for the conflicting data in different SCI models.

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

“…Entinostat is a narrow-spectrum HDAC inhibitor of class I HDAC that has been shown to possess neuroprotective functions in brain ischemia and intracerebral hemorrhage (Mota et al, 2020;Bonsack and Sukumari-Ramesh, 2021). A large number of studies have confirmed that HDACs are involved in the physiologic processes that occur following SCI (Zhang H. et al, 2018;Chen et al, 2018;Hendrix et al, 2020;Zhou et al, 2020). Recent studies have shown that HDACs tend to increase in PBMC nuclear extracts of SCI patients, including increased HDAC3 in PBMCs from SCI patients (Ma et al, 2015).…”

“…In our study, we found that HDAC1, HDAC2, and HDAC3 expressions were enhanced in the spinal cord after SCI and entinostat decreased HDAC1 and HDAC3 expressions but without affecting the HDAC2 expression. Entinostat, another class I HDAC inhibitor, has potential neuroprotective effects in brain damage (Zhang H. et al, 2018;Hendrix et al, 2020;Bonsack and Sukumari-Ramesh, 2021). Entinostat reduces NF-κB-p65 expression and nuclear accumulation as well as the neuroinflammatory response (TNF-α and IL-1β levels) in the hippocampus, which causes the improvement of postoperative cognitive dysfunction in rats (Wu et al, 2019).…”

“…Tubastatin A promotes acetylation and stabilization of microtubules and thus restores transport function in nocodazoletreated cells and SCI mice by inhibiting HDAC 6, which may contribute to restored autophagic flux and increased axonal length (Zheng et al, 2020). Hendrix et al have found specific HDAC 8 inhibition with PCI-34051 reduces the number of perilesional macrophages as measured by histologic analyses but does not improve functional recovery after SCI (Hendrix et al, 2020). Entinostat, a member of the benzamide group, is a narrow-spectrum HDAC inhibitor and affects class I HDAC with limited effect on HDAC 8, which is already used for conducting several phase I/II clinical trials on cancers (Kiany et al, 2020).…”

Neurological recovery and antioxidant effect of erythropoietin for spinal cord injury: A systematic review and meta-analysis

“…The Collaborative Approach to Meta Analysis and Review of Animal Data From Experimental Stroke (CAMARADES) 10-item checklist were used to assess the quality and design of the studies by two independent investigators (30). The CAMARADES list includes the following: (1) Two reviewers assessed the risk of bias. Bias was marked as high or low risk, as well as "unclear" indicated that the risk of bias was unclear.…”

“…Spinal cord injury (SCI) is an injury to the spinal cord caused by trauma or disease, which may lead to alterations to the normal motor, sensory or autonomic function of the spinal cord ( 1 , 2 ). Traumatic SCI is a disastrous event associated with high morbidity and mortality ( 3 ).…”