Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation

Abstract

BackgroundEpilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Seizure-induced TLR4/MYD88 signaling plays a critical role in activating microglia and triggering neuron apoptosis. SAHA is a histone deacetylase inhibitor that regulates gene expression by increasing chromatin histone acetylation. In this study, we investigated the role of SAHA in TLR4/MYD88 signaling in a rat seizure model.ResultsSprague–Dawley rats with kainic acid (KA)-induced seizures were treated with SAHA. The expression of TLR4, MYD88, NF-κB P65 and IL-1β in hippocampus was detected at hour 2 and 6 and day 1, 2, and 3 post seizure. SAHA pretreatment increased seizure latency and decreased seizure scores. The expression levels of TLR4, MYD88, NF-κB and IL-1β increased significantly in both activated microglia and apoptotic neurons after KA treatment. The effects were attenuated by SAHA. Chromatin immunoprecipitation assays indicated that the H3 histone acetylation levels significantly decreased while H3K9 levels significantly increased in the KA treatment group. The H3 and H3K9 acetylation levels returned to control levels after SAHA (50 mg/kg) pretreatment. There was a positive correlation between the expression of TLR4 and the acetylation levels of H3K9.ConclusionsHistone deacetylase inhibitor SAHA can suppress seizure-induced TLR4/MYD88 signaling and inhibit TLR4 gene expression through histone acetylation regulation. This suggests that SAHA may protect against seizure-induced brain damage.

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

“…HDAC inhibition did not affect H3 association or acetylation in this region either ( Fig. 5A), which has also been observed by others (44)(45)(46)(47)(48). Since housekeeping genes are constitutively active, it is possible that the histones associated with these genes are already maximally acetylated and therefore not influenced by SAHA treatment.…”

Chronic demyelination-induced seizures

“…In mouse models of epilepsy, microglia/macrophages express so-called M1 pro-inflammatory cytokines such as inducible nitric oxide synthase, tumor necrosis factor α, interleukin (IL)-1β, IL-6, and IL-12 as well as lymphocyte co-stimulatory molecules cluster of differentiation (CD) 80, CD86, and major histocompatibility complex II at high levels (Eyo et al, 2017). M1 polarization may be attributable to signaling by TLR4/MYD88 and purinergic receptors, which play a prominent role in many neuroinflammatory states (Zhou et al, 2013; Hu and Mao, 2016). Determining the phenotype of microglia/macrophages that appear in CA1 during chronic demyelination may help clarify their role in seizures secondary to MS.…”

Role of Microglia TLRs in Neurodegeneration

“…Different stimuli may lead to increased expression of microglia TLRs, such as hypoxia (Smith et al, 2013 ; Yao et al, 2013 ), LPS (Kielian et al, 2005 ; Yousif et al, 2018 ), Poly(I:C; Yousif et al, 2018 ), kainic acid (Wang et al, 2015 ; Hu and Mao, 2016 ), α-synuclein (Béraud et al, 2011 ; Daniele et al, 2015 ) and amyloid beta (Aβ; Jana et al, 2008 ; Richard et al, 2008 ; Caldeira et al, 2017 ).…”