Elsevier

Brain Research Reviews

Volume 57, Issue 2, 14 March 2008, Pages 398-409
Brain Research Reviews

Review
Regenerative potential of allopregnanolone

https://doi.org/10.1016/j.brainresrev.2007.08.010Get rights and content

Abstract

The neuroendocrine status of the brain has been linked to the quality of the aging process, to the risk of Alzheimer's disease and to progression of neurodegenerative pathology. Data from multiple levels of analysis ranging from in vitro cellular models to in vivo animal models to clinical investigations indicate that the decline of neurosteroids play a key role in successful aging and prevention of neurodegenerative disease Alzheimer's. Among the neurosteroids in decline during aging is allopregnanolone (APα, a metabolite of progesterone, which is reduced in the serum, plasma and brain of aged vs. young subjects. Further, Alzheimer's disease (AD) victims exhibit an even greater reduction in plasma and brain levels of APα relative to age-matched neurologically normal controls. Our earlier work has shown that APα is a neurogenic agent for rodent hippocampal neural progenitors and for human neural progenitor cells derived from the cerebral cortex. Our ongoing research seeks to determine the neurogenic potential of APα in the triple transgenic mouse model of Alzheimer's disease (3×TgAD) as AD related pathology progresses from imperceptible to mild to severe. Initial analyses suggest that APα may maintain the regenerative ability of the brain, modify progression of AD related pathology and reverse learning and memory deficits in 3×TgAD mice. This review summarizes current APα research in different animal models, neural progenitor regeneration within a degenerative milieu and the challenge for developing neuroregenerative therapeutics.

Section snippets

Unmet therapeutic need: prevention and delay of Alzheimer's disease

Currently more than 5 million Americans suffer from Alzheimer's which costs approximately $100 billion dollars per year (Fillit and Hill, 2005, Hebert et al., 2001, Refolo and Fillit, 2006). Approximately, 360,000 new cases of AD occur each year in the United States. Conservative projections predict that the prevalence of AD will nearly quadruple within just 43 years, at which point 14 million older Americans are expected to have AD (Mount and Downton, 2006). If no effective preventive

Microenvironment supporting neurogenesis during aging and AD progression

In the developing brain, most stem cells and microenvironments are spatially shifting and are temporally transient as the cellular and molecular programs of neurogenesis and morphogenesis are “assembled and disassembled” (Alvarez-Buylla and Lim, 2004). In contrast to the undulating milieu of stem cell zones in the embryonic nervous system, the adult brain restricts neural stem cells and their proliferation to select microenvironments. These specialized domains, the subventricular zone (SVZ) of

Challenges of regenerative therapeutics for Alzheimer's disease

While the therapeutic potential of neural stem cells is great, so too are the challenges. AD is a diffuse degenerative disease with pathology and neuronal death occurring in multiple brain regions. Four regions within the AD brain show evidence of aberrant entry into the cell cycle predictive of neuronal loss: the hippocampus, subiculum, locus caeruleus and dorsal raphe nucleus (Busser et al., 1998). In addition to these sites is the late stage loss of cholinergic neurons likely due to the loss

The role of progesterone and allopregnanolone on growth factor expression

Gonadal hormones are potent regulators of growth factor expression. Best known is estrogen and progesterone regulation of BDNF (Berchtold et al., 2001, Gibbs, 1999, Jezierski and Sohrabji, 2003, Scharfman and Maclusky, 2005, Toran-Allerand, 1996). As expected, growth factors are increased during pregnancy. In particular EGF, IGF and TGFβ1 are all upregulated at the same time progesterone and hence APα are increased (Lennard et al., 1995a, Lennard et al., 1995b, Lennard et al., 1998, Stewart et

PK/PD/Tox relevant to developing allopregnanolone as a small molecule, blood–brain barrier permeable neurogenic agent

Unlike large molecular weight growth factors, such as FGF and neurotrophins, which do not readily pass the blood–brain barrier, APα with a steroidal chemical structure, 3α-hydroxy-5α-pregnan-20-one, low molecular weight of 318.49 and hydrophobic properties (LogP value = 4.2) easily penetrates the blood–brain barrier. APα induces several CNS effects including antianxiolytic, antiseizure and our data indicate neurogenesis. Our GC/MS data demonstrate that APα is significantly and linearly increased

APα as a regenerative factor to promote functional neurogenesis and diminish Alzheimer's pathology

Recently, we demonstrated that APα promoted in vitro proliferation of human and rat neural progenitors and mouse hippocampal neurogenesis in vivo in a dose-dependent and steroid-specific manner (Wang et al., 2005). The proliferative effect of APα we observed in rat hippocampal neural progenitor cells and human cerebral cortical neural progenitor cells in vitro (Wang et al., 2005) was also observed in rodent cerebellar granule cells which also undergo proliferation during development (Keller et

The effects of APα on learning and memory

It has been well known that learning and memory is influenced by fluctuations in steroid hormones (Frye et al., 2007, Mayo et al., 1993, Mayo et al., 2005, Walf et al., 2006). Interestingly, the age and AD disease related decline of APα is also paralleled by the learning and memory loss. Therefore, it was of particular interest to investigate the effects of APα on learning and memory.

In the past decades, several groups have investigated the effects of APα on behavior, particularly on learning

Therapeutic potential of APα as a regenerative factor

The small molecular weight, steroidal chemical structure and hydrophobic properties of APα make it an ideal molecule to penetrate the blood–brain barrier. Our discovery that APα is a proliferative agent for neural progenitor cells in vitro and in vivo suggests that APα could act to promote proliferation in the AD brain. Further, the very preliminary finding that APα could delay or diminish AD pathology burden suggests that APα could be a multifaceted regenerative therapeutic to both promote the

Acknowledgments

This work was supported by a grant from the Institute for the Study of Aging/Alzheimer's Drug Discovery Foundation to and the Kenneth T. and Eileen Norris Foundation to RDB.

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