Abstract
Glucocorticoids (GCs) such as dexamethasone (DEX) or betamethasone are repeatedly administered for up to a month to prematurely born infants as a treatment for chronic lung dysfunction. Results of clinical trials have shown that the use of GCs in these infants induces long-term deficits in neuromotor function and cognition. We have previously shown that a single exposure to clinically relevant doses of DEX or other GCs in the mouse during a period corresponding to the human perinatal period produces a dramatic increase in apoptotic cell death of neural progenitor cells in the developing cerebellum. To provide a model approximating more chronic clinical dosing regimens, we evaluated possible behavioral effects resulting from repeated exposures to DEX and subsequent GC-induced neuronal loss where neonatal mouse pups were injected with 3.0 mg/kg DEX or saline on postnatal days 7, 9, and 11 (DEX3 treatment). Adult, DEX3-treated mice exhibited long-term, possibly permanent, neuromotor deficits on a complex activity wheel task, which requires higher-order motor co-ordination skills. DEX3 mice exhibited impaired performance on this task relative to saline controls in each of two independent studies involving separate cohorts of mice. Histopathology studies utilizing stereological neuronal counts conducted in behaviorally-tested mice showed that the DEX3 treatment resulted in a significant decrease in the number of neurons in the internal granule layer (IGL) of the cerebellum, although the number of neurons in the Purkinje cell layer were unchanged. The results suggest that multiple neonatal DEX exposures can produce chronic deficits in fine motor co-ordination that are associated with cerebellar IGL neuronal loss.
Highlights
There is currently much controversy regarding the clinical use of glucocorticoids (GCs) for the treatment of respiratory dysfunction associated with premature birth [1]
Subsequent pair-wise comparisons indicated that the body weights of the DEX3 and saline control groups differed significantly on postnatal day (PND) 9, 11, 14, 21, and
[F(1,24) = 13.32, p = 0.0013], while the effects of Gender and Group by Gender interactions were not significant, documenting that DEX3 treatment resulted in a significant reduction (20%) in neurons from the internal granule cell layer (IGL) (Figure 6E). These results suggest the apoptotic death of external granule layer (EGL) neural progenitor cell (NPC) results in a decrease in the number of IGL granule cells produced
Summary
There is currently much controversy regarding the clinical use of glucocorticoids (GCs) for the treatment of respiratory dysfunction associated with premature birth [1]. Much of this concern has arisen after several placebo-controlled double blind clinical studies have shown that the chronic postnatal use of GC therapy can cause permanent neuromotor and cognitive deficits [2,3]. It is of great concern that an estimated 10% of prematurely born infants still receive this treatment [4]. Overall it is estimated that approximately 7–10% of all pregnant women receive prenatal GC therapy [7]. Despite the large percentage of humans exposed to this therapy and the mounting concerns regarding its safety, surprisingly little is known about how GC exposure can produce neuropathological sequelae and long-term behavioral deficits
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