Endogenous as well as exogenous androgens and oestrogen have neuroprotective properties. Oestrogen is formed locally in neural tissue from precursor androgens. In the brain, the expression of aromatase, the enzyme that catalyses the conversion of androgens to oestrogen, is restricted, under normal circumstances, to specific neuronal populations involved in neuroendocrine control and in the modulation of reproductive or sexually dimorphic behaviours. However, the expression of both the enzyme aromatase and oestrogen receptor alpha is induced in reactive astrocytes after brain injury. This indicates that astroglia react to brain lesions by producing oestrogen and increasing their sensitivity to the steroid. Intracerebroventricular infusion of an oestrogen receptor antagonist (ICI 182,780) blocks neuroprotective effects of the hormone in vivo. Furthermore, pharmacological or genetic inactivation of aromatase results in an increased neuronal death after brain injury, suggesting that aromatase induction in reactive astrocytes, and the resultant higher local levels of oestrogen, play a neuroprotective role. Oestrogen precursors synthesized in the central nervous system, mainly by glia, are also neuroprotective. The neuroprotective effects of pregnenolone, dehydroepiandrosterone and testosterone are prevented by the inhibition of aromatase, suggesting that oestrogen synthesis by glia mediates the neuroprotective effects of oestrogen precursors. Furthermore, astroglia may participate in the neuroprotective mechanisms of oestrogen by the synthesis of growth factors, such as insulin-like growth factor-I (IGF-I), that are involved in oestrogen effects in the brain. IGF-I receptor is necessary for the neuroprotective effect of estradiol and interactions of oestrogen receptor alpha and IGF-I receptor are involved in the activation of neuronal survival signalling pathways. In summary, astroglia appear to play a critical role in the neuroprotective actions of oestrogen.
This study has been supported by the Commission of the European Communities, specific RTD programme ''Quality of Life and Management of Living Resources'', QLK6-CT-2000-00179.
22 - 24 Mar 2004
British Endocrine Societies