Pharmacological Research 52 (2005) 119–132 Review From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens Diana Amantea a , Rossella Russo b , Giacinto Bagetta a,* , Maria Tiziana Corasaniti b a Department of Pharmacobiology, University of Calabria, Via P. Bucci, Ed. Polifunzionale, Arcavacata di Rende (CS), Italy b Department of Pharmacobiological Sciences, University “Magna Graecia” of Catanzaro, Italy Accepted 14 March 2005 Abstract Recent studies have highlighted that female sex hormones represent potential neuroprotective agents against damage produced by acute and chronic injuries in the adult brain. Clinical reports have documented the effectiveness of estrogens to attenuate symptoms associated with Parkinson’s disease, and to reduce the risk of Alzheimer’s disease and cerebrovascular stroke. This evidence is corroborated by numerous experimental studies documenting the protective role of female sex hormones both in vitro and in vivo. Accordingly, estrogens have been shown to promote survival and differentiation of several neuronal populations maintained in culture, and to reduce cell death associated with excitotoxicity, oxidative stress, serum deprivation or exposure to -amyloid. The neuroprotective effects of estrogens have been widely documented in animal models of neurological disorders, such as Alzheimer’s and Parkinson’s diseases, as well as cerebral ischemia. Although estrogens are known to exert several direct effects on neurones, the cellular and molecular mechanisms implicated in their protective actions on the brain are not completely understood. Thus, on the basis of clinical and experimental evidence, in this review, we discuss recent findings concerning the neuronal effects of estrogens that may contribute to their neuroprotective actions. Both estrogen receptor-dependent and -independent mechanisms will be described. These include modulation of cell death regulators, such as Bcl-2, Akt and calpain, as well as interaction with growth factors, such as BDNF, NGF, IGF-I and their receptors. The anti-inflammatory effects of estrogens will also be described, namely their ability to reduce brain levels of inflammatory mediators, cytokines and chemokines. Finally, a brief overview about receptor-independent mechanisms of neuroprotection will aim at describing the antioxidant effects of estrogens, as well as their ability to modulate neurotransmission. © 2005 Elsevier Ltd. All rights reserved. Keywords: Estrogen; Neuroprotection; Estrogen replacement therapy (ERT) Contents 1. Introduction ..................................................................................................... 120 2. Clinical and epidemiological studies ............................................................................... 120 3. Experimental studies ............................................................................................. 121 3.1. In vitro studies ............................................................................................. 121 3.2. In vivo studies ............................................................................................. 121 4. Mechanisms implicated in estrogen-mediated neuroprotection ........................................................ 122 4.1. ER-mediated mechanisms of neuroprotection ................................................................. 122 4.2. Effects of estrogen on molecules involved in the regulation of programmed cell death ............................. 123 4.3. Regulation of growth factors by estrogens .................................................................... 123 4.4. Anti-inflammatory activity of estrogens ...................................................................... 124 * Corresponding author. Tel.: +39 0984 493462; fax: +39 0984 493462. E-mail address: gbagett@tin.it (G. Bagetta). 1043-6618/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2005.03.002