Rationale for the Use of Soy Phytoestrogens for Neuroprotection

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Introduction 105

The Hypothesis and Experiments 107

The Rationale Supporting the Hypothesis and Experiments 110

Discussion of Data Obtained to Date 112

Complexities in the Existing Literature 113

Looking into the Future 115

Acknowledgments 116

References 116


The purpose of this chapter is to stimulate thinking, not just about the potential benefits of the soy phytoestrogens in the brain, but also about the larger issue of the role of diet in general in determining late life health. This chapter will discuss experimental approaches taken to address whether soy phytoestrogens, or isoflavones, can have neuroprotective actions in the mammalian brain. The structural similarity between the soy isoflavones and the natural estrogen, 170-estradiol (Figure 8.1), has been the rationale for experiments by many others that have shown that soy isoflavones can have beneficial effects in models of cardiovascular disease (Anthony et al., 1996; Clarkson et al., 1997), breast cancer, and prostate cancer (both

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17p -estradiol

Figure 8.1 Structural similarities between the soy isoflavone genistein and 1713-estradiol.


Figure 8.1 Structural similarities between the soy isoflavone genistein and 1713-estradiol.

reviewed in Lamartiniere and Fritz, 1998). Indeed, the brain is the last frontier for testing the efficacy of soy or any phytoestrogen as an estrogen alternative, although epidemiology and experimental data provide strong rationale for both estrogen-replacement and identification of estrogen alternatives for maintaining post-menopausal brain health (Sherwin, 1988: Sherwin, 1997; McEwen and Alves, 1999; Tang et al., 1996; Toran-Allerand et al., 1999; Yaffe et al., 1998).

Our intrinsic scientific interest in the brain has been the role of the neuronal cytoskeletal elements, the microtubules, in neuronal function and viability, and the consequences of estrogen deprivation to this cytoskeletal system. Hyperphosphory-lation of the microtubule-associated protein tau has been linked with Alzheimer's disease (AD) pathology, in that the neurofibrillary tangles (NFT) that are histologic markers for AD brain are comprised of tau that is hyperphosphorylated at selected sites (Goedert et al., 1992; Kosik et al., 1988). The dogma is that although these phosphorylations are normal phosphorylations, the extent to which the hyperphos-phorylated sites are modified in tau in the NFTs renders the tau less able to associate with microtubules. These in turn become more susceptible to depolymerization (Hong et al., 1998; Kim et al., 1986), leading to loss of neuronal morphology and, ultimately, function (Figure 8.2).

Thus, the identification of the molecular consequences of postmenopausal estrogen loss is critical, particularly identification of those which are attenuated by estrogen-replacement, or estrogen-like compounds such as the soy isoflavones. This is particularly true for estrogen loss, since it is a risk factor, not a causal factor, for AD. Obviously, not every elderly woman becomes afflicted with AD, although every woman experiences menopausal estrogen reduction. Epidemiological data obtained with postmenopausal women in the U.S. suggested, however, that even limited estro-

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