Gonadal Hormones, Neurosteroids, and Clinical Progestins as Neurogenic Regenerative Agents: Therapeutic Implications

Liu, Lifei; Brinton, Roberta Dı́az

doi:10.1002/9783527633968.ch17

Cited by 4 publications

(7 citation statements)

References 153 publications

(129 reference statements)

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“…These regions retain regenerative potential throughout the life span with marked declines in aged brain (Kuhn et al, 1996; Cameron and McKay, 1999; reviewed in Liu and Brinton, 2010). Adult mammalian neurogenesis has been confirmed in humans (Eriksson et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Dynamic neural stem-cell proliferation zones apparent in the developing central nervous system are also present in the adult brain, primarily restricted to the dentate gyrus subgranular zone (SGZ; Altman and Das, 1965 ; Cameron et al, 1993 ; reviewed in Liu and Brinton, 2010 ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle (Altman, 1969 ; Luskin, 1993 ; reviewed in Liu and Brinton, 2010 ). These regions retain regenerative potential throughout the life span with marked declines in aged brain (Kuhn et al, 1996 ; Cameron and McKay, 1999 ; reviewed in Liu and Brinton, 2010 ). Adult mammalian neurogenesis has been confirmed in humans (Eriksson et al, 1998 ).…”

Section: Introductionmentioning

confidence: 99%

“…The number of new granule neurons generated each month is 6% of the total size of the granule cell population and 30–60% of the size of the afferent and efferent populations. Although most newborn granule cells do not survive, 3% of these cells are replaced every month which corresponds to ∼0.1% per day in young adult mice and rats (Kempermann et al, 1997 ; Cameron and McKay, 1999 ; Liu and Brinton, 2010 ). In the rat dentate gyrus, 85% of the granule cells are formed postnatally (Bayer and Altman, 1974 ).…”

Section: Introductionmentioning

confidence: 99%

“…Neurosteroids bind to GABA A R at sites that differ from GABA, benzodiazepines, ethanol, and barbiturate binding sites and can act as positive or negative modulators of GABA A R function (Gee et al, 1987 , 1988 ; reviewed in Liu and Brinton, 2010 ). Allopregnanolone (APα; 3α-hydroxy-5α-pregnan-20-one; also known as AP, Allo, or THP) is a potent positive allosteric activator of the GABA A R channels which at nanomolar concentrations enhances the action of GABA at GABA A R and at higher concentrations directly activates GABA A R. APα binds to two transmembrane sites of the heteropentameric GABA A R (Hosie et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

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Neuroregenerative Mechanisms of Allopregnanolone in Alzheimer’s Disease

Irwin¹,

Wang²,

Chen³

et al. 2012

Front. Endocrin.

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The proliferative pool and regenerative potential of neural stem cells diminishes with age, a phenomenon that may be exacerbated in prodromal and mild Alzheimer’s disease (AD) brains. In parallel, the neuroactive progesterone metabolite, allopregnanolone (APα), along with a host of other factors, is decreased in the AD brain. Results of preclinical analyses demonstrate that APα is a potent inducer of neural progenitor proliferation of both rodent and human derived neural progenitor cells in vitro. In vivo, APα significantly increased neurogenesis within the subgranular zone of the dentate gyrus and subventricular zone of the 3xTgAD mouse model. Functionally, APα reversed the learning and memory deficits of 3xTgAD mice prior to and following the onset of AD pathology and was comparably efficacious in aged normal mice. In addition to inducing regenerative responses in mouse models of AD, APα significantly reduced beta-amyloid burden, beta-amyloid binding alcohol dehydrogenase load, and microglial activation. In parallel, APα increased markers of white matter generation and cholesterol homeostasis. Analyses to determine the optimal treatment regimen in the 3xTgAD mouse brain indicated that a treatment regimen of APα once per week was optimal for both inducing neurogenesis and reducing AD pathology. Pharmacokinetic analyses indicated that APα is rapidly increased in both plasma and brain following a single dose. APα is most efficacious when administered once per week which will contribute to its margin of safety. Further, analyses in both animals and humans have provided parameters for safe APα dosage exposure in humans. From a translational perspective, APα is a small molecular weight, blood brain barrier penetrant molecule with substantial preclinical efficacy data as a potential Alzheimer’s therapeutic with existing safety data in animals and humans. To our knowledge, APα is the only small molecule that both promotes neural progenitor regeneration in brain and simultaneously reduces AD pathology burden.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Neuroregenerative Mechanisms of Allopregnanolone in Alzheimer’s Disease

Irwin¹,

Wang²,

Chen³

et al. 2012

Front. Endocrin.

Self Cite

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“…The neurogenic functions of hCG/LH may be mediated (or coordinated) via the upregulation in the synthesis of P 4 or other sex steroids, as P 4 has been found to be essential for the specification of pluripotent stem cells into a neuronal phenotype (Gallego et al 2010; Gallego, et al 2009). The requirement for progestagens and estrogens for the growth, development and day-to-day maintenance and connectivity of neurons is well described (Liu and Diaz Brinto 2011). …”

Section: Gonadotropins Gnrh1 and Developmental Neurogenesismentioning

confidence: 99%

The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease

Atwood

Bowen²

2015

Hormones and Behavior

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Sex hormones are the physiological factors that regulate neurogenesis during embryogenesis and continuing through adulthood. These hormones support the formation of brain structures such as dendritic spines, axons and synapses required for the capture of information (memories). Intriguingly, a recent animal study has demonstrated that induction of neurogenesis results in the loss of previously encoded memories in animals (e.g. infantile amnesia). In this connection, much evidence now indicates that Alzheimer’s disease (AD) also involves aberrant re-entry of post-mitotic neurons into the cell cycle. Cell cycle abnormalities appear very early in the disease, prior to the appearance of plaques and tangles, and explain the biochemical, neuropathological and cognitive changes observed with disease progression. Since sex hormones control when and how neurons proliferate and differentiate, the endocrine dyscrasia that accompanies menopause and andropause is a key signaling event that impacts neurogenesis and the acquisition, processing, storage and recall of memories. Here we review the biochemical, epidemiological and clinical evidence that alterations in endocrine signaling with menopause and andropause drive the aberrant re-entry of post-mitotic neurons into an abortive cell cycle with neurite retraction that leads to neuron dysfunction and death. When the reproductive axis is in balance, luteinizing hormone (LH), and its fetal homolog, human chorionic gonadotropin (hCG), promote pluripotent human and totipotent murine embryonic stem cell and neuron proliferation. However, strong evidence supports menopausal/andropausal elevations in the ratio of LH:sex steroids as driving aberrant mitotic events mediated by the upregulation of tumor necrosis factor, amyloid-β precursor protein processing towards the production of mitogenic Aβ, and the activation of Cdk5, a key regulator of cell cycle progression and tau phosphorylation (a cardinal feature of both neurogenesis and neurodegeneration). Cognitive studies also demonstrate the negative consequences of a high LH:sex steroid ratio on human cognitive performance. Prospective epidemiological and clinical evidence in humans supports lowering the ratio of circulating gonadotropins-GnRH to sex steroids in reducing the incidence of AD and halting cognitive decline. Together, these data support endocrine dyscrasia and the subsequent loss of cell cycle control as an important etiological event in the development of neurodegenerative diseases including AD, stroke and Parkinson’s disease.

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