Introduction: Dehydroepiandrosterone (DHEA) is an androgen with trophic effects on brain growth , and anti-glucocorticoid actions that diminish neurotoxicity and oxidative stress [2-5]. We therefore determined if DHEA is produced de novo in the developing brain of the spiny mouse (Acomys caharinus), a precocial rodent known to synthesize this C19 steroid .
Methods: Expression of P450c17 and cytochrome b5 (Cytb5) - the enzyme and accessory protein responsible for the synthesis of DHEA - and the glucocorticoid receptor (GR) were determined in 35 day gestation fetal (term = 39 days), neonatal (day of birth) and adult (80 days old) brains by immunocytochemistry. Double-label immunofluorescence was used to determine co-localisation in neurons (NeuN), astrocytes (GFAP) or oligodendrocytes (CNPase). P450c17 bioactivity was determined using radioimmunoassay of conversion of pregnenolone (PREG) to DHEA by explants of fetal, neonatal and adult brain.
Results: Fetal brain explants produced significantly more DHEA after 48 h in culture (22.46±2.00 ng/mg) than adult brain explants (5.04±2.04 ng/mg; p<0.0001, independent ANOVA). The GR, P450c17 and Cytb5 were diffusely expressed in white matter tracts and synaptic boutons in the fetal and neonatal brainstem; P450c17 was also co-expressed in midbrain neurons, a region showing GR neuronal expression predominantly in fetal samples; P450c17 and GR were expressed in pontine nuclei on the day of birth. In contrast, P450c17 expression was detected only in the trigeminal motor nucleus and the corpus callosum of the adult brain.
Conclusion: These results show that the spiny mouse brain can synthesize DHEA in late gestation and the early neonatal period. The predominant expression of P450c17 and Cytb5 in the brain stem and midbrain suggests that DHEA may promote axonal growth of differentiated neurons during development. Local synthesis may protect these regions against glucocorticoid-mediated neurotoxicity, particularly in white matter and pathways associated with the cerebellum and spinal cord.