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J. Biol. Chem., Vol. 279, Issue 13, 13086-13094, March 26, 2004

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Involvement of Insulin/Phosphoinositide 3-Kinase/Akt Signal Pathway in 17-Estradiol-mediated Neuroprotection^*

Xiaorui Yu, Raju V. S. Rajala¶||, James F. McGinnis¶||, Feng Li||, Robert E. Anderson¶||, Xiaorong Yan||, Sheng Li||, Rajesh V. Elias||, Ryan R. Knapp||, Xiaohong Zhou||, and Wei Cao||**

From the Departments of Ophthalmology and ^¶Cell Biology, ^||Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 and the Department of Biochemistry and Molecular Biology, School of Medicine Xi'an Jiaotong University, 710061 Xi'an, China

In the present study, we tested the hypothesis that 17-estradiol (E2) is a neuroprotectant in the retina, using two experimental approaches: 1) hydrogen peroxide (H₂O₂)-induced retinal neuron degeneration in vitro, and 2) light-induced photoreceptor degeneration in vivo. We demonstrated that both E2 and 17-estradiol (E2) significantly protected against H₂O₂-induced retinal neuron degeneration; however, progesterone had no effect. E2 transiently increased the phosphoinositide 3-kinase (PI3K) activity, when phosphoinositide 4,5-bisphosphate and [³²ATP] were used as substrate. Phospho-Akt levels were also transiently increased by E2 treatment. Addition of the estrogen receptor antagonist tamoxifen did not reverse the protective effect of E2, whereas the PI3K inhibitor LY294002 inhibited the protective effect of E2, suggesting that E2 mediates its effect through some PI3K-dependent pathway, independent of the estrogen receptor. Pull-down experiments with glutathione S-transferase fused to the N-Src homology 2 domain of p85, the regulatory subunit of PI3K, indicated that E2 and E2, but not progesterone, identified phosphorylated insulin receptor -subunit (IR) as a binding partner. Pretreatment with insulin receptor inhibitor, HNMPA, inhibited IR activation of PI3K. Systemic administration of E2 significantly protected the structure and function of rat retinas against light-induced photoreceptor cell degeneration and inhibited photoreceptor apoptosis. In addition, systemic administration of E2 activated retinal IR, but not the insulin-like growth factor receptor-1, and produced a transient increase in PI3K activity and phosphorylation of Akt in rat retinas. The results show that estrogen has retinal neuroprotective properties in vivo and in vitro and suggest that the insulin receptor/PI3K/Akt signaling pathway is involved in estrogen-mediated retinal neuroprotection.

Received for publication, December 5, 2003

^* This work was supported by National Center for Research Sources Grant P20 RR17703; National Institutes of Health Grants EY014427, EY13050, EY00871, EY04149, EY12190, and EY06973; by a Jules and Doris Stein professorship and an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness; by the Foundation Fighting Blindness, Baltimore, MD; by the Samuel Roberts Nobel Foundation, Inc., Ardmore, OK; and by the Presbyterian Health Foundation, Oklahoma City, OK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Ophthalmology, University of Oklahoma Health Sciences Center, Dean A. McGee Eye Institute, 608 Stanton L. Young Blvd., Oklahoma City, OK 73104. Tel.: 405-271-3370; Fax: 405-271-3721; E-mail: wei-cao{at}ouhsc.edu.

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