Dexamethasone induces apoptosis of progenitor cells in the subventricular zone and dentate gyrus of developing rat brain

Abstract

The use of dexamethasone in premature infants to prevent and/or treat bronchopulmonary dysplasia adversely affects neurocognitive development and is associated with cerebral palsy. The underlying mechanisms of these effects are multifactorial and likely include apoptosis. The objective of this study was to confirm whether dexamethasone causes apoptosis in different regions of the developing rat brain. On postnatal day 2, pups in each litter were randomly divided into the dexamethasone-treated (n = 91) or vehicle-treated (n = 92) groups. Rat pups in the dexamethasone group received tapering doses of dexamethasone on postnatal days 3-6 (0.5, 0.25, 0.125, and 0.06 mg/kg/day, respectively). Dexamethasone treatment significantly decreased the gain of body and brain weight and increased brain caspase-3 activity, DNA fragments, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and cleaved caspse-3-positive cells at 24 hr after treatment. Dexamethasone increased cleaved caspse-3-positive cells in the cortex, thalamus, hippocampus, cerebellum, dentate gyrus, and subventricular zone. Double-immunofluorescence studies show that progenitor cells in the subventricular zone and dentate gyrus preferentially undergo apoptosis following dexamethasone exposure. These results indicate that dexamethasone-induced apoptosis in immature cells in developing brain is one of the mechanisms of its neurodegenerative effects in newborn rats.

Bacterial Meningitis: Insights Into Pathogenesis and Evaluation of New Treatment Options: A Perspective from Experimental Studies

“…These results may in part explain the discrepancy between increased hippocampal apoptosis in experimental models and improved clinical outcome in some patient groups [20,133]. Use of corticosteroids in the younger patient population should be of special concern, since it was shown that dexamethasone caused neurodegeneration in the neonatal rat brain by inducing neuronal progenitor cell death [140].…”

Maternal treatment with glucocorticoids modulates gap junction protein expression in the ovine fetal brain

“…In addition, prenatal dexamethasone treatment of pregnant dams with 0.4 mg/kg on days 18–21 of gestation, resulted in increases in the number of cleaved caspase-3-positive neurons in the amygdala suggesting that prenatal dexamethasone induces neuronal apoptosis (Zuloaga et al, 2011). Postnatal treatment of rat pups with dexamethasone also results in apoptosis the developing brain (Bhatt et al, 2013). In contrast to these findings in nonhuman primates and pregnant dams (Zuloaga et al, 2011, Bhatt et al, 2013), we have shown that maternal treatment with a single course of antenatal glucocorticoids in the same paradigm as in the current study significantly reduces apoptosis and caspase 3 activity in the fetal sheep brain (Malaeb et al, 2009).…”

“…Postnatal treatment of rat pups with dexamethasone also results in apoptosis the developing brain (Bhatt et al, 2013). In contrast to these findings in nonhuman primates and pregnant dams (Zuloaga et al, 2011, Bhatt et al, 2013), we have shown that maternal treatment with a single course of antenatal glucocorticoids in the same paradigm as in the current study significantly reduces apoptosis and caspase 3 activity in the fetal sheep brain (Malaeb et al, 2009). In addition, although exposure to multiple courses of dexamethasone did not affect the number of apoptotic cells, caspase 3 activity was reduced (Malaeb et al, 2009).…”

Dexamethasone but not the equivalent doses of hydrocortisone induces neurotoxicity in neonatal rat brain

“…In our previous studies, we have investigated and discussed the adverse effects of Dex on body weight and brain weight, caspase-3 activity, and apoptotic changes (11). The current report explores the differences between Dex and HC.…”

“…Brain specimens from DexTD, HCTD, and vehicle groups were prepared as described previously (11). At PD7, pups were anesthetized with pentobarbital and received transcardiac perfusion with icecold saline and then with 4% paraformaldehyde in PBS.…”