Harmful Effects of Neonatal Epileptic Seizures on Cerebrovascular Functions: Does Sex Matter?

Abstract

There is a growing interest in the potential contribution of sex‐related variables to cerebrovascular functions in healthy and sick neonates. Epileptic seizures, the most common adverse neurological event in human newborns, may lead to cerebrovascular injury and abnormalities in cerebral blood flow regulation. Clinical studies suggest that male neonates are more susceptible to seizures, with a higher incidence of neurological complications. Cerebral vascular health is an important contributing factor to brain homeostasis and neuronal health. Newborn piglets provide a valuable and translationally relevant animal model for studying the cerebrovascular effects of epileptic seizures in the neonatal brain. This study in newborn pigs (2–5 days old) was designed to investigate whether sex‐related differences contribute to systemic parameters and cerebrovascular functions in: 1) control healthy animals and 2) piglets subjected to bicuculline‐induced epileptic seizures leading to prolonged cerebral vascular dysfunction during the delayed postictal period. After a 48‐h recovery period from epileptic seizures, postictal cerebrovascular functions were tested using intravital microscopy via the closed cranial window technique. We recorded the responses of small‐ and medium‐sized pial cerebral arterioles (50–100 μm) to a battery of vasodilator stimuli including: A) endothelium‐dependent hypercapnia and bradykinin; B) dual endothelium/astrocyte‐dependent stimuli glutamate, ionotropic glutamate receptor agonist quisqualic acid, and hemin; C) astrocyte‐dependent vasodilator adenosine diphosphate, and D) endothelium/astrocyte‐independent vasodilator sodium nitroprusside (SNP). We found no sex‐related differences in cardiovascular parameters (mean arterial blood pressure, heart rate), arterial blood gases, or core body temperature in either control or postictal groups of newborn piglets. A significant reduction (50–70%) in responses of pial arterioles to endothelium‐ and/or astrocyte‐dependent vasodilators was observed 48 h after seizures (delayed postictal period) in both male and female piglets. In piglets of both sexes, vasodilation to SNP was preserved during the delayed postictal period, suggesting that vascular smooth muscle contractility was not affected by seizures. An antioxidant and cytoprotective compound, the carbon‐monoxide (CO)‐releasing molecule CORM‐A1 (3 mg/kg i.p.) that was administered shortly before and/or during seizures, prevented postictal loss of cerebrovascular functions in both male and female piglets. Overall, we observed no sex‐specific differences in selected systemic cardiovascular parameters and cerebrovascular dilator functions in control and epileptic newborn pigs. In both male and female piglets, epileptic seizures lead to severe cerebral vascular dysfunction during the delayed postictal period. Antioxidant therapy with CORM‐A1 is neuroprotective in both male and female newborn pigs because it effectively prevents deleterious effects of epileptic seizures on cerebral blood flow regulation in a sex‐independent manner.Support or Funding InformationThe study was supported by NIH/NHLBI/NINDS.