Effect of the HDAC Inhibitor, Sodium Butyrate, on Neurogenesis in a Rat Model of Neonatal Hypoxia–Ischemia: Potential Mechanism of Action

Abstract

Neonatal hypoxic–ischemic (HI) brain injury likely represents the major cause of long-term neurodevelopmental disabilities in surviving babies. Despite significant investigations, there is not yet any known reliable treatment to reduce brain damage in suffering infants. Our recent studies in an animal model of HI revealed the therapeutic potential of a histone deacetylase inhibitor (HDACi). The neuroprotective action was connected with the stimulation of neurogenesis in the dentate gyrus subgranular zone. In the current study, we investigated whether HDACi—sodium butyrate (SB)—would also lead to neurogenesis in the subventricular zone (SVZ). By using a neonatal rat model of hypoxia–ischemia, we found that SB treatment stimulated neurogenesis in the damaged ipsilateral side, based on increased DCX labeling, and restored the number of neuronal cells in the SVZ ipsilateral to lesioning. The neurogenic effect was associated with inhibition of inflammation, expressed by a transition of microglia to the anti-inflammatory phenotype (M2). In addition, the administration of SB increased the activation of the TrkB receptor and the phosphorylation of the transcription factor—CREB—in the ipsilateral hemisphere. In contrast, SB administration reduced the level of HI-induced p75 NTR . Together, these results suggest that BDNF–TrkB signaling plays an important role in SB-induced neurogenesis after HI. These findings provide the basis for clinical approaches targeted at protecting the newborn brain damage, which may prove beneficial for treating neonatal hypoxia–ischemia.

Communications Between Peripheral and the Brain-Resident Immune System in Neuronal Regeneration After Stroke

“…Supplement of SCFAs in drinking water ameliorates microglia dysfunction caused by reduced complexity or depletion of gut microbiota (113). In ischemic conditions, SCFAs promote the phenotype transition of microglia and exert neurogenesis and neurite outgrowth permissive effects by activating BDNF-TrkB signaling (114,115). HDAC inhibition also protects white matter by polarizing microglia/macrophage into the protective type through the GSK3β/PTEN/Akt axis (114).…”

Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE

“…The activation of PKCε influences a number of signaling mechanisms, such as modulating the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) [36]. CREB has been proved to be a transcription factor that participates in anti-apoptosis, antiinflammation, and other pathological processes in cerebral ischemia injury, subarachnoid hemorrhage, and HIE [37,38]. CREB is an important downstream signaling molecule that mediates the biological effects of CSF1 in neurons and macrophages.…”

White matter injury in the neonatal hypoxic‐ischemic brain and potential therapies targeting microglia

“…The injection of IL‐10, a potent stimulator of M2 microglial polarization, exerts a neuroprotective effect on newborn mice with a cystic preterm brain injury (Mesples et al., 2003). In addition, microglia may secrete growth factors in response to injury to the developing brain, such as IGF‐1, galectin‐3, and BDNF (Doverhag et al., 2010; Jaworska et al., 2019; Wlodarczyk et al., 2017). Interestingly, both TNF‐α and IL‐1β, which were previously mentioned as factors that impair OL functions and are secreted by microglial cells, were shown to play dual roles in OL development.…”