High vulnerability of estrogen-producing retinal cells to excitotoxic insult: downregulation of P450 aromatase activity

Numerous studies, including ours, suggest a role of neurosteroids and/or neuroactive steroids in neuronal cell death. Our studies have been particularly focused on the role served by neurosteroids in excitotoxic retinal cell death as neurodegenerative or neuroprotective agents. Excitotoxicity is an important mechanism in the pathogenesis of ocular diseases such as glaucoma, ischemia/hypoxic attack, and optic neuropathy, as well as in several brain neurodegenerative disorders. We have pointed out that pregnenolone sulfate (PS) acts as a neurotoxic agent with agonist actions at NMDA receptors, whilst DHEA/S, progesterone, 3alfa5betaS and 17beta-estradiol function as neuroprotective agents (Guarneri P et al., 1998; Cascio C et al., 2000, 2002). The role of PS is especially supported by the evidence that NMDA receptor activation induces PS synthesis before retinal death occurs, and blockade of P450scc involved in the synthesis with aminoglutethimide (AMG) attenuates excitotoxicity (Guarneri et al., 1998). Here, we demonstrate that exposure of the isolated retina to either NMDA or PS also induces downregulation of P450aromatase activity and consequent low production of 17beta-estradiol both in the presence or absence of testosterone which is the primary precursor of retinal estradiol synthesis. The excitotoxic-mediated increase in PS and decrease in estradiol synthesis appear to be confined to different retinal cells since P450aromatase is primarily located at the outer and inner nuclear layers and P450scc at the ganglion cell layer. Consistent with this, blockade of P450scc activity by AMG completely prevents ganglion cell death, and the inhibitor of aromatase potentiates retinal damage. Thus, excitotoxic-mediated retinal cell death implies diverse steroidogenic pathways at different subsets of retinal cells. The results substantiate the neuroprotective role of estradiol and likely point to a higher vulnerability of estrogenic-producing retinal cells to excitotoxic events.