Abstract
Background: Endogenous steroids are known to be essential for normal brain development. Pre-and postnatal glucocorticoids however, are associated with increased risk for adverse neurological outcome through mechanisms that are not clear, but may lead to alterations of cell structure and function.
Objective: The present study tests the hypothesis that prenatal dexamethasone given at critical points in gestation will result in increased neuronal nuclear Ca++-influx, leading to activation of caspase -3 and 9 which triggers the apoptotic pathway and that this mechanism is dependent on gestational age.
Design/Methods: Two groups of fetal guinea pigs were studied, at 35 (n=8) and 45 (n=8) days gestation. Saline (Sa), 0.5ml/dose, or dexamethasone (Dx), 0.4mg/kg/dose was injected i.p. into the mother daily x 2 days. Fetal guinea pig brains were harvested at 72 hours post Sa or Dx injection. Nuclei were isolated and ATP-dependent Ca++-influx was determined. Cytosolic caspase-3, and -9 activity was determined. Caspase activity was determined spectrofluorometrically and expressed as nmoles/mg protein/hr.
Results: Ca++-influx at 35d was 6.42+/-2.0 (Sa) and 7.42+/-3.4 (Dx), an increase of 16%; at 45d was 5.63+/-2.3 (Sa) and 10.5+/-2.1 (Dx), an increase of 80%. Caspase-3 activity at 35d was 13.3 +/-1.3 (Sa) and 13.9+/-1.9 (Dx); at 45d was 12.8+/-0.8 (Sa) and 9.53+/-1.01 (Dx), a decrease of 25%. Caspase-9 activity at 35d was 3.52+/-0.3 (Sa) and 3.39+/-0.2 (Dx); at 45d was 3.46+/-0.2 (Sa) and 2.49+/-0.2 (Dx), a decrease of 28%. The data show that antenatal Dexamethasone resulted in increased Ca++-influx in neuronal nuclei of fetal guinea pigs without altering caspase-3 or -9 activity.
Conclusions: We conclude that Dexamethasone activates neuronal nuclear membrane mechanisms that initiate the apoptotic cascade and increase with gestational age. We speculate that Dexamethasone modifies nuclear membrane mechanisms of Ca++ influx and leads to cellular injury through an apoptotic pathway independent of caspase expression.
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Anday, E., Handley, S., Ashraf, Q. et al. 8 Effect of Dexamethasone on Neuronal Nuclear Calcium Influx in the Developing Fetal Guinea Pig. Pediatr Res 58, 355 (2005). https://doi.org/10.1203/00006450-200508000-00037
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DOI: https://doi.org/10.1203/00006450-200508000-00037
