Abstract
Hypoxic-ischemic encephalopathy (HIE) resulting from asphyxia in the peripartum period is the most common cause of neonatal brain damage and can result in significant neurologic sequelae, including cerebral palsy. Currently therapeutic hypothermia is the only accepted treatment in addition to supportive care for infants with HIE, however, many additional neuroprotective therapies have been investigated. Of these, glucocorticoids have previously been shown to have neuroprotective effects. HIE is also frequently compounded by infectious inflammatory processes (sepsis) and as such, the infants may be more amenable to treatment with an anti-inflammatory agent. Thus, the present study investigated dexamethasone and hydrocortisone treatment given after hypoxic-ischemic (HI) insult in neonatal rats via intracerebroventricular (ICV) injection and intranasal administration. In addition, we examined the effects of hydrocortisone treatment in HIE after lipopolysaccharide (LPS) sensitization in a model of HIE and sepsis. We found that dexamethasone significantly reduced rat brain infarction size when given after HI treatment via ICV injection; however it did not demonstrate any neuroprotective effects when given intranasally. Hydrocortisone after HI insult also significantly reduced brain infarction size when given via ICV injection; and the intranasal administration showed to be protective of brain injury in male rats at a dose of 300 µg. LPS sensitization did significantly increase the brain infarction size compared to controls, and hydrocortisone treatment after LPS sensitization showed a significant decrease in brain infarction size when given via ICV injection, as well as intranasal administration in both genders at a dose of 300 µg. To conclude, these results show that glucocorticoids have significant neuroprotective effects when given after HI injury and that these effects may be even more pronounced when given in circumstances of additional inflammatory injury, such as neonatal sepsis.
Highlights
Worldwide, intrapartum-related events or birth asphyxia, which results in hypoxic-ischemic encephalopathy (HIE), is the leading cause of death among term infants [1]
When hydrocortisone was given both by ICV injection and intranasal instillation in both the HI and HI with sepsis models, it demonstrated significant neuroprotection. Our study examined both dexamethasone and hydrocortisone treatments via ICV injection and intranasal administration after HI injury in a neonatal rat model of HIE
We show a significant reduction in infarction size with 0.1 μg dexamethasone administration via ICV injection 2 h post-HI event, suggesting that direct neural activation of the glucocorticoid receptor (GR) may play a significant role in perinatal neuroprotection from HI injury
Summary
Intrapartum-related events or birth asphyxia, which results in hypoxic-ischemic encephalopathy (HIE), is the leading cause of death among term infants [1]. Despite the large morbidity and mortality associated with HIE, currently, the only approved and validated treatment in addition to supportive care for infants with HIE is therapeutic hypothermia (whole body cooling). This therapy requires specialized centers which limits its availability and its use is dependent on specific criteria, such as gestational age, injury severity and, most importantly, time from the event to the initiation of treatment (must be initiated within 6 h from the time of the event) [4]. One potential reason for the improved success of dexamethasone in the more recent studies may be its method of direct brain delivery via intracerebroventricular (ICV) injection with lower doses rather than the traditional delivery method via intraperitoneal (IP) injection with higher doses, which inherently results in more systemic effects and side effects
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