Estrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications for Basic Science Understanding of Estrogen Signaling and Development of Estrogen Modulators with a Dual Therapeutic Profile

Abstract

The present study sought to determine the characteristics of ICI 182,780 (Faslodex) action in rat primary hippocampal neurons. We first investigated the neuroprotective efficacy of ICI 182,780 against neurodegenerative insults associated with Alzheimer's disease and related disorders. Dose-response analyses revealed that ICI 182,780, in a concentration-dependent manner, significantly promoted neuron survival following exposure to either excitotoxic glutamate (200 μM)- or β-amyloid_1–42 (1.5 μM)-induced neurodegeneration of hippocampal neurons. At a clinically relevant concentration of 50 ng/ml, ICI 182,780 exerted nearly maximal neuroprotection against both insults with efficacy comparable with that induced by the endogenous estrogen 17β-estradiol. Thereafter, we investigated the impact of 50 ng/ml ICI 182,780 on mechanisms of 17β-estradiol-inducible neuronal plasticity and neuroprotection. Results of these analyses demonstrated that ICI 182,780 directly induced a series of rapid intracellular Ca²⁺ concentration ([Ca²⁺]_i) oscillations in a pattern comparable with that of 17β-estradiol. In addition, ICI 182,780 exerted dual regulation of the glutamate-induced rise in [Ca²⁺]_i identical to that induced by 17β-estradiol. Further analyses demonstrated that ICI 182,780 induced significant activation of extracellular signal-regulated kinase 1/2 and Akt (protein kinase B) and significantly increased expression of spinophilin and Bcl-2, with efficacy comparable with neurons treated with 17β-estradiol. Taken together, results of these in vitro analyses of ICI 182,780 provide direct evidence of an estrogenic agonist profile of ICI 182,780 action in rat hippocampal neurons. Therapeutic development of neuroselective estrogen receptor modulators that mimic ICI 182,780 is discussed with respect to the potential of safe and efficacious alternatives to estrogen therapy for the prevention of postmenopausal cognitive decline and late-onset Alzheimer's disease.