The use of a specific HDAC8 inhibitor to improve functional recovery after spinal cord injury

Abstract

The poor outcome after spinal cord injury (SCI) is mainly due to the excessive inflammatory response elicited after trauma. Using histone deacetylase (HDAC) inhibitors is a promising approach to suppress excessive inflammation and improve SCI outcome. In this study, it is hypothesized that specific HDAC8 inhibition improves functional recovery after SCI as HDAC8 inhibition is shown to have anti-inflammatory effects.

The phenotype of pre-polarized M1 and M2 macrophages treated with the specific HDAC8 inhibitor PCI-34051 was investigated in vitro. The role of HDAC8 in macrophage polarization was determined using the Griess assay and by western blot for iNOS and Arg-1. In addition, the effect of PCI-34051 on functional recovery in a spinal cord T-cut hemisection injury model was analyzed using the Basso Mouse Scale. Furthermore, spinal cords were immunohistochemically examined.

Western blot reveals no significant differences in iNOS and Arg-1 expression. Furthermore, PCI-34051 does not affect NO production by LPS-stimulated BMDMs in vitro, as demonstrated by the Griess assay. In addition, motor function recovery after systemic PCI-34051 administration was evaluated in vivo, but no significant differences in BMS score were observed. Immunohistochemical analysis suggests no effect on lesion size, astrogliosis, demyelination and immune cell infiltration into the injured spinal cord after PCI-34051 administration. However, a role for HDAC8 in the regulation of the macrophage phenotype in vivo was illustrated.