Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

Abstract

Background: Hyperglycemia is a common metabolic problem in extremely low-birth-weight preterm infants. Neonatal hyperglycemia is associated with increased mortality and brain injury. Glucose-mediated oxidative injury may be responsible. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair and cell survival. However, PARP-1 overactivation leads to cell death. NF-κB is coactivated with PARP-1 and regulates microglial activation. The effects of recurrent hyperglycemia on PARP-1/NF-κB expression and microglial activation are not well understood. Methods: Rat pups were subjected to recurrent hypoinsulinemic hyperglycemia of 2 h duration twice daily from postnatal (P) day 3-P12 and killed on P13. mRNA and protein expression of PARP-1/NF-κB and their downstream effectors were determined in the cerebral cortex. Microgliosis was determined using CD11 immunohistochemistry. results: Recurrent hyperglycemia increased PARP-1 expression confined to the nucleus and without causing PARP-1 overactivation and cell death. NF-κB mRNA expression was increased, while IκB mRNA expression was decreased. inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expressions were decreased. Hyperglycemia significantly increased the number of microglia. conclusion: Recurrent hyperglycemia in neonatal rats is associated with upregulation of PARP-1 and NF-κB expression and subsequent microgliosis but not neuronal cell death in the cerebral cortex.

Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus

“…The volume of injection was 0.01 mL/g for the first injection and 0.005 mL/g for the second injection. Our previous study has demonstrated that this model induces hyperglycemia, beginning at 5 min after the first dextrose injection, with spontaneous resolution 120 min later, 14 likely due to stimulation of insulin secretion from the pancreas. Pups assigned to the P30-control group were subcutaneously injected with an equivalent volume of normal saline at the corresponding times.…”

“…Loss of neurons (where Glu is predominantly localized) and/or increased number of astrocytes (where Gln is predominantly localized) is unlikely to explain the lower Glu/Gln ratio. The hyperglycemia model used in the present study is not associated with neuronal loss . Unchanged levels of NAA, the marker of neuronal integrity (Figure ), and unchanged astrocyte number (Supplementary Figure) in the hyperglycemia groups also rule out neuronal loss and/or astrocytosis as the explanation for decreased Glu/Gln ratio.…”

“…However, there is a wide variation among clinicians in the criteria used for insulin therapy and the target blood glucose ranges, leading to continuous hyperglycemia in many infants. Published and unpublished studies from our laboratory and other laboratories demonstrate that the two hyperglycemia models have similar adverse effects (oxidative stress and inflammation) on the brain regions.…”

“…Pups assigned to the hyperglycemia groups were subjected to hyperglycemia twice a day at 08:00 and 16:00 for 10 consecutive days (20 hyperglycemia episodes in total) from P3 to P12 using a previously described method. 14,15 These postnatal ages were chosen because of their similarity to the stage of hippocampal development in the ELGAN (P3) and full-term (P12) human infant, respectively. 9,27 Pups were separated from the dams, weighed and subcutaneously injected with 30% dextrose (3 mg/g body weight; moderate-HG group) or 50% dextrose (5 mg/g body weight; severe-HG group).…”

“…10,12,13 Previous studies from our laboratory and other laboratories have demonstrated that recurrent hyperglycemia during the first two postnatal weeks causes oxidative stress, DNA damage, inflammation and microgliosis in the cerebral cortex and hippocampus of rats. 14,15 Oxidative stress and inflammation may negatively influence hippocampal dendritogenesis and function. Furthermore, in adult rats, hyperglycemia alters glycogen and lactate metabolism in the hippocampus.…”