Vitamin D improves functional outcomes in neonatal hypoxic ischemic male rats treated with N -acetylcysteine and hypothermia

Abstract

Hypothermia treatment neuroprotects approximately 50% of neonates who present with moderate to severe hypoxic ischemic encephalopathy (HIE). N-acetylcysteine (NAC), a potent antioxidant, is neuroprotective in combination with hypothermia in neonatal hypoxia-ischemia (HI) female rats, but less protective in males. Vitamin D is a neurosteroid, which may provide immunomodulation and improve outcomes for both sexes. We investigated the efficacy of this combination of drugs with hypothermia after severe HI, as well as potential mechanisms of vitamin D effects in the transition to chronic inflammation. DOL 7 rats were randomized to sham, or HI and hypothermia treated with either saline (HYPO), NAC (50 mg/kg/d, HNAC), or HNAC plus 1,25-dihydroxy-vitamin D (0.1 μg/kg/d, HNAC + VitD) daily for 2 weeks. A second set of animals were randomized and treated for 11 days to investigate vitamin D metabolism and inflammatory mediators. Rats treated with HNAC + VitD performed significantly better on tests of strength and use of affected limb, adaptive sensorimotor skills, motor sequence learning, and working memory than either HYPO or HNAC, particularly benefiting male rats. Significantly fewer rats in the HNAC + VitD group had severe hemispheric volume loss. HI injury decreased serum vitamin D at 11 days and induced the enzyme that deactivates vitamin D in the hippocampus, particularly in males. Persistent vitamin D dysregulation was seen in both hippocampi in males, which was not reversed by hypothermia. Vitamin D in combination with hypothermia and NAC supports functional recovery in both sexes of neonatal rats significantly better than hypothermia alone or hypothermia and NAC in this severe HI model.

N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats

“…Furthermore, NAC has been investigated as a safe neuroprotectant in animal models and human neonates with hypoxic ischemic injury, infection, and white matter injury. 22,34,37,38 In addition, we have demonstrated that NAC can significantly increase [GSH] in the basal ganglia of neonates 5 days after hypoxic ischemic birth, mitigating ongoing oxidative stress. 34 Cerebral oxidative stress has been well described during acute opioid withdrawal.…”

N-acetylcysteine inhibits bacterial lipopeptide-mediated neutrophil transmigration through the choroid plexus in the developing brain

“…NAC has been shown to ameliorate postnatal or laterlife neurological outcome in different models of perinatal diseases, when administrated to the mother before birth or postnatally to the pups [1,4,7,33,62]. It has been the object of a positive clinical trial in the context of chorioamnionitis [26].…”

“…Neutrophils produce large amounts of reactive oxygen species which play a central role in the inflammatory response [34]. We and others previously showed that the antioxidant therapeutical compound Nacetylcysteine (NAC) protects the neonatal brain from injury in animals subjected to lipopolysaccharide exposure and hypoxia-ischemia [33,62]. This drug also improves the glutathione-dependent antioxidant machinery at the ChPs [20].…”

Vitamin D deficiency in relation to the poor functional outcomes in nondiabetic patients with ischemic stroke

“…Third, the observational study does not allow advancing any cause and effect relationships. However, a previous study suggested that vitamin D in combination with hypothermia supported functional recovery in both sexes of neonatal rats with severe hypoxic ischemic encephalopathy [ 40 ]. In addition, we did not collect data on sun exposure, dietary intake of vitamin D, and outdoor physical activity, so we could not determine the association of those factors with serum 25(OH) D levels and outcomes of Chinese patients with acute ischemic stroke.…”