Phytoestrogenic Formulations for Alleviation or Prevention of Neurodegenerative Diseases

Abstract

Select phytoestrogen pharmaceutical compositions and methods of use for promoting neurological health and prevention of age-related neurodegeneration, such as AD, have been developed. These select phytoestrogen formulations are composed of a number of plant-derived estrogenic molecules and / or their structural analogues and exhibit binding preference to ERβ over ERα and agonist activity in the brain. These ERβ-selective phytoestrogen formulations cross the blood-brain-barrier and promote estrogen-associated neurotrophism and neuroprotection mechanisms in the brain, without activating proliferative mechanisms in the reproductive tissues and are therefore devoid of other estrogen-associated problematic aspects. The select phytoestrogen formulations are therapeutically useful to both women and men for sustaining neurological health and preventing age-related cognitive decline and neurodegenerative disorders, such as AD. These are administered enterally, transdermally, transmucosally, intranasally or parenterally, in a dosage effective to prevent or alleviate neuronal damage, effect neuronal regeneration or sustain viability, increase expression of anti-apoptotic proteins, and / or decrease indicators of Alzheimer's Disease. The formulations preferably contain combinations of compounds, and can be formulated for daily, sustained, delayed or weekly / monthly administration. In a preferred embodiment, these are administered to women who are in menopause or post menopausal, most preferably early in menopausal.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Ser. No. 60 / 819,849 mailed by express mail label no. ER 455959795 US on Aug. 1, 2006; U.S. Ser. No. 60 / 889,920 filed Feb. 14, 2007, and U.S. Ser. No. 60 / 943,190 filed Jun. 11, 2007. The disclosure(s) in the application(s) listed above are herein incorporated by reference.STATEMENT REGARDING FEDERALLY FUNDED RESEARCH [0002] This work was supported by National Institute of Mental Health Intramural Research Program (P.J.S.) and Grant MH67159 (R.D.B.), National Institute of Aging Grants AG06647 (J.H.M.), AG16765 (J.H.M., A.C.G.), and AG14751 and AG026572 (R.D.B.), and the Kenneth T. and Eileen L. Norris Foundation (R.D.B.).BACKGROUND OF THE INVENTION [0003] The demographics suggest that we face a devastating increase in the prevalence of AD, reinforcing the immediate need for basic and translational neuroscience to develop safe and efficacious ET and HT regimens for the brain. Of those affected with ...

AI Technical Summary

Benefits of technology

[0017] These are administered enterally, transdermally, transmucosally, intranasally or parenterally, in a dosage effective to prevent or alleviate neuronal damage, effect neuronal regeneration or sustain viability, increase expression of anti-apoptotic proteins, and/or decrease indicators of Alzhei

Problems solved by technology

However, a double danger exists for women.

Data from both basic science analyses and clinical studies indicate a “healthy cell bias” of estrogen action in the neurons / brains, suggesting that ET / HT acts as an effective preventative therapeutic strategy for age-related cognitive decline and neurodegenerative disorders, such as Alzheimer's disease (“AD”), while it is not an effective treatment strategy.

Another key issue challenging PIT is the optimal composition.

Moreover, while ET / HT has long been used in postmenopausal women to delay or reverse some of the problems associated with menopause, epidemiological and clinical studies have uncovered potential long-term risks related to this therapy.

Taken together, these data establish a potential therapeutic application for ERβ as a pharmacological target to promote memory function and neuronal defense mechanisms against age-related neurodegeneration such as Alzheimer's disease (AD), while avoiding activating untoward estrogenic proliferative effects in the breast and uterus, although this might be at the cost of lower efficacy due to the lack of activation of ERβ in the brain.

However, a potential disadvantage of an ERβ-selective ligand is the lack of activation of ERα in bone, as ERα has been demonstrated to mediate estrogen regulation of bone density.

In addition, as compared with ERα, ERβ is less effective in mediating the sexual characteristics of estrogen action in reproductive tissues, avoiding activating untoward estrogenic proliferative effects in the breast and uterus.

However, this safety may be at the cost of lower efficacy, due to the lack of activation of ERα in the brain.

The therapeutic efficacy of phytoestrogens in the brain remains controversial.

On the other hand, a recent clinical trial revealed that a soy protein supplement that contains a mixture of phytoestrogens did not show improved cognitive function in postmenopausal women, when treatment was initiated at the age of 60 years or older.

Another issue that can substantially impact the efficacy of a mixture of phytoestrogens action in the brain is the formulation of phytoestrogens, since when administered alone, a number of phytoestrogens were protective to neurons from neurodegenerative insults.

The ineffectiveness of a complex formulation of phytoestrogens in promoting beneficial effects of estrogen in brain, such as a soy-derived preparation, may also arise from antagonizing actions among the different phytoestrogens, in addition to the possible ER antagonism, likely from the activation of both ERα and ERβ in the same context.

Co-administration of an ERα-selective agonist and an ERβ-selective agonist is less effective than treatment with either agonist alone in various neuroprotective measurements.

These findings indicate that although both ERα and ERβ contribute to estrogen promotion of neuronal survival, simultaneous activation of both ER subtypes, ERα and ERβ, in the same context may diminish the efficacy.

Moreover, selective targeting of ERβ potentially reduces antagonistic actions that may occur in a complex soy-derived preparation.

Images