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Editors Selection IGR 14-3

Basic Research: E2 neuroprotective activity

Comment by Abbot Clark on:

21962 17β-Estradiol prevents retinal ganglion cell loss induced by acute rise of intraocular pressure in rat, Russo R; Cavaliere F; Watanabe C et al., Progress in Brain Research, 2008; 173: 583-590

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Lowering IOP is the mainstay of glaucoma therapy, because it prevents the development and progression of glaucomatous optic neuropathy and retinopathy. However, risk factors other than IOP have been identified, and considerable attention has been focused on mechanisms that directly protect retinal ganglion cells (RGCs). 17β-estradiol (E2) and estrogen analogs protect brain neurons from a wide variety of insults, including ischemia and excitotoxicity. Russo et al. (1647) evaluated the effect of systemically administered E2 in a rat model of acute retinal ischemia/reperfusion. IOP was elevated to 120 mmHg for 50 minutes, which inhibited ocular blood flow, followed by return to normal pressure. This insult caused a significant loss of cells in the RGC layer and an increase in vitreous glutamate levels, which peaked shortly after reperfusion. Pretreatment with E2 (0.2 mg/kg) 30 minutes prior to the ischemia insult partially inhibited the loss of cells in the RGC layer 24 hours post insult (28% in vehicle control vs 7% in the E2-treated animals) and also inhibited reperfusion associated increase in intravitreal glutamate. Pretreatment with a selective estrogen receptor antagonist, ICI 182-780, partially blocked the E2 neuroprotective activity and suppression of glutamate release. However, the weak estrogen agonist 17β-estradiol suppressed the late phase release of glutamate after repurfusion, suggesting that some of estrogen's neuroprotective activity may be independent of the estrogen receptor. Although pretreatment with E2 protected the retina 24 hours after the ischemic insult, longer term protection and post-ischemia treatment were not studied. This work complements previous studies showing the retinal neuroprotective activity of estradiol. E2 protected cultured RGCs from glutamateinduced (Kumar et al. Free Radic Biol Med 2005; 38: 1152-1163) and H₂O₂-induced (Yu et al. J Biol Chem 2004; 279: 13086-13094) cytotoxicity. E2 also protected RGCs in vivo in the DBA/2J mouse model of pigmentary glaucoma (Zhou et al. Dev Neurobiol 2007; 67: 603-616) and in a model of axonopathy-induced RGC death (Nakazawa et al. Brain Res 2006; 1093: 141-149). Although the Russo study suggested that some of the E2 neuroprotective activity in the acute ischemia model was via inhibition of glutamate release, E2 has other neuroprotective activities including protecting mitochondria (Simpkins & Dykens Brain Res Rev 2008; 57: 421-430). Clearly, the retinal neuroprotective properties of E2 and estrogen analogs warrant additional study as a potential new therapeutic option for the treatment of glaucoma.

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