Class I histone deacetylase (HDAC) inhibitor CI-994 promotes functional recovery following spinal cord injury

Abstract

Spinal cord injury (SCI) induces severe and long-lasting neurological disability. Accumulating evidence has suggested that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults and deficits in the central nervous system. In the present study, we assessed the effect of the class I HDAC inhibitor CI-994 in a mouse model of SCI. Following SCI, mice were treated with either dimethyl sulfoxide (control vehicle) or 1, 10, or 30 mg/kg CI-994. Level of acetylated histone H3 expression was increased in the motor cortex and spinal cord of 10 mg/kg CCI-994-treated mice after SCI. CI-994 increased histone H3 acetylation in the myeloperoxidase-positive neutrophils and CD68-positive microglia/macrophages in the spinal cord. Although it did not appear to contribute to corticospinal tract axonal reorganization, intraperitoneal injection of CI-994 promoted behavioral recovery following SCI. Furthermore, administration of CI-994 suppressed neutrophil accumulation, inflammatory cytokine expressions, and neuronal loss as early as 3 days following injury. Thus, our findings indicate that HDAC inhibitors may improve functional recovery following SCI, especially during the early stages of the disease.

Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats

“…Histone hyperacetylation of chromatin by HDAC inhibition using HDAC inhibitors (HDACi) has been shown to improve learning and memory by impacting synaptic plasticity (Graff et al, 2014; Graff & Tsai, 2013). Additionally, the novel use of HDACi has been proposed in a wide variety of neurological conditions such as post‐traumatic stress disorder (Whittle & Singewald, 2014), depression (Misztak, Panczyszyn‐Trzewik, & Sowa‐Kucma, 2018), spinal cord injury (Zhang, Fujita, Matsuzaki, & Yamashita, 2018), and addiction (Anderson et al, 2019; Kennedy et al, 2013; Kennedy & Harvey, 2015) due to the ability of HDACi to penetrate the central nervous system and attenuate the negative symptoms associated with these conditions through epigenetic and non‐epigenetic mechanisms.…”

Niacin Inhibits Apoptosis and Rescues Premature Ovarian Failure

“…Because acetylation covalently modifies many proteins, it has strong chromatin-modifying potential in DNA repair, transcription and replication. Some evidence has suggested that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults and deficits in the central nervous system [28,29], and some protein acetylation can help cell survive and resist to oxidative stress [30].…”

Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome

“…Although a relatively broad effect of CI-994 on gene expression has been demonstrated in vivo, it is being used in several clinical trials for anti-cancer therapy having proven inhibitory potency of epithelial-mesenchymal transition processes 35 . Accumulating evidence also suggests that CI-994 provides neuroprotective effects in the central nervous system and cell survival in vitro 36 . Regarding brain function in WT mice no effect of CI-994 treatment has been seen in the open field 26 .…”