Abstract
Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.
Highlights
In many intracerebral hemorrhage (ICH) patients, the symptoms of neurological deficits continue to worsen gradually, even after the removal of hematoma in many patients [1]
Valproate sodium (VPA) significantly inhibits the toxicity of hemin and reduces nerve cell death in both cortical cells and the brain through decreasing heme oxygenase-1 (HO-1) protein expression [6], neuroinflammation, and perihematomal cell death in the ICH model via transcriptional activation following histone deacetylase (HDAC) inhibition [7]
We demonstrated that VPA treatment improved blood brain barrier (BBB) integrity in the ICH model, which was accompanied by a decrease in the activity of p-NFκB, matrix metalloproteinases 9 (MMP9), IL-6, and tumor necrosis factorα (TNFα) as well as an increase in the level of endothelial junction proteins, which in turn, ameliorated short-term and long-term neurological impairments after ICH
Summary
In many ICH patients, the symptoms of neurological deficits continue to worsen gradually, even after the removal of hematoma in many patients [1] This indicates that the secondary injury of brain tissue is the main factor of aggravation and poor prognosis after ICH. Several studies have confirmed that VPA protects the nervous system through a variety of signaling pathways. It is a traditional antiepileptic drug, and its antiepileptic mechanism is related to the decreased neuronal excitability caused by a variety of comprehensive factors [2]. Based on the current research and treatment status of the intracerebral hemorrhage, this study is aimed at clarifying the protective effect and potential mechanism of VPA on BBB integrity after ICH and supplying a prospective option for the patients with ICH
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