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.
Highlights
Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures
Further gene expression analyses by Real-time qPCR confirmed that Toll-like-receptor 4 (TLR4), MYD88, NF-κB P65, and IL-1β mRNA levels were consistent with protein level tendencies (Fig. 5). These results suggested that SAHA could suppress seizures-induced TLR4/MYD88 signaling
The results suggested that the expression of TLR4 was dependent on the acetylation levels of H3K9; SAHA led to hypoacetylation of H3K9, which in turn resulted in downregulation of the expression of TLR4
Summary
Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Seizureinduced TLR4/MYD88 signaling plays a critical role in activating microglia and triggering neuron apoptosis. We investigated the role of SAHA in TLR4/MYD88 signaling in a rat seizure model. Epilepsy is among the most common brain disorders [1]. Previous studies suggest that inflammation plays an important role in epilepsy development [2,3,4,5,6]. Seizureinduced inflammation can generate a negative feedback loop on neurons [7]. Expressed in microglia [13,14,15], TLR4 is closely involved in microglia inflammation responses [16]. Inhibiting TLR4-mediated microglia activation in inflammatory responses could have neuroprotective effects. It has been shown that systemic administration of kainic acid (KA) can induce epileptic seizures, which causes neuroinflammation or neuronal cell death in the hippocampus CA1 and CA3 regions in animals [17,18,19,20]
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