Abstract
BackgroundNeonatal hypoxic-ischemic brain damage, characterized by tissue loss and neurologic dysfunction, is a leading cause of mortality and a devastating disease of the central nervous system. We have previously shown that vitexin has been attributed various medicinal properties and has been demonstrated to have neuroprotective roles in neonatal brain injury models. In the present study, we continued to reinforce and validate the basic understanding of vitexin (45 mg/kg) as a potential treatment for epilepsy and explored its possible underlying mechanisms.MethodsP7 Sprague-Dawley (SD) rats that underwent right common carotid artery ligation and rat brain microvascular endothelial cells (RBMECs) were used for the assessment of Na+-K+-Cl− co-transporter1 (NKCC1) expression, BBB permeability, cytokine expression, and neutrophil infiltration by western blot, q-PCR, flow cytometry (FCM), and immunofluorescence respectively. Furthermore, brain electrical activity in freely moving rats was recorded by electroencephalography (EEG).ResultsOur data showed that NKCC1 expression was attenuated in vitexin-treated rats compared to the expression in the HI group in vivo. Oxygen glucose deprivation/reoxygenation (OGD) was performed on RBMECs to explore the role of NKCC1 and F-actin in cytoskeleton formation with confocal microscopy, N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide, and FCM. Concomitantly, treatment with vitexin effectively alleviated OGD-induced NKCC1 expression, which downregulated F-actin expression in RBMECs. In addition, vitexin significantly ameliorated BBB leakage and rescued the expression of tight junction-related protein ZO-1. Furthermore, inflammatory cytokine and neutrophil infiltration were concurrently and progressively downregulated with decreasing BBB permeability in rats. Vitexin also significantly suppressed brain electrical activity in neonatal rats.ConclusionsTaken together, these results confirmed that vitexin effectively alleviates epilepsy susceptibility through inhibition of inflammation along with improved BBB integrity. Our study provides a strong rationale for the further development of vitexin as a promising therapeutic candidate treatment for epilepsy in the immature brain.
Highlights
Neonatal hypoxic-ischemic brain damage, characterized by tissue loss and neurologic dysfunction, is a leading cause of mortality and a devastating disease of the central nervous system
The present study firstly showed that vitexin is beneficial to the treatment of HI insult through disturbing the Na+-K+-Cl− co-transporter1 (NKCC1)/F-actin pathway, which potentially protects against the severity of blood-brain barrier (BBB) collapse
Our results showed an upregulation of the protein and mRNA expression of NKCC1 in the peri-ischemic brain tissue
Summary
Neonatal hypoxic-ischemic brain damage, characterized by tissue loss and neurologic dysfunction, is a leading cause of mortality and a devastating disease of the central nervous system. Perinatal hypoxic-ischemic encephalopathy (HIE) secondary to perinatal asphyxia remains a major cause of neonatal mortality and is associated with long-term neurologic comorbidities both in the late preterm and term neonate [1]. The mainstay of treatment for HIE remains comprehensive treatment, including hyperbaric oxygen therapy and mild hypothermia therapy, and medication. This therapy has been shown to improve survival and neurodevelopmental outcome, the neuroprotective response is limited by timing of initiation and severity of encephalopathy [10]. It is an urgent need to develop effective agents that target vulnerable periods in HIE-induced neonatal epilepsy
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