Neuroscience
Brinton RD & Wang JM (2006). Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res., 3(3), 185-190.
Department of Molecular Pharmacology and Toxicology and Program in Neuroscience, Pharmaceutical Science Center, 1985 Zonal Avenue, University of Southern California, Los Angeles, CA 90033, USA.
A major challenge not yet addressed by current therapeutic interventions for Alzheimer's disease (AD) is the regeneration of lost neurons and neural circuitry to restore cognitive function. Therapies that lead to cessation of the degenerative process still leave the brain riddled with deteriorated neural circuits and reduced neuron number. The discovery of neurogenesis in the adult brain and the regenerative potential of neural stem cells holds the promise for restoration of neural populations and regeneration of neural circuits necessary for cerebral function. While the regenerative potential of neural stem cells is great, so too is the challenge of delivering neural stem cells to the brain. Basic science analyses and human trials indicate that constituents of microenvironments within the brain determine the neurogenic potential, phenotypic differentiation of neural stem cells and magnitude of the neural stem cell pool. Multiple analyses have documented that dentate neurogenesis is regulated by multiple growth factors which are abundant during development and which dramatically decline with age. While the cause(s) of age-associated decline in neurogenesis remains to be fully determined, loss in growth factors, FGF-2, IGF-1 and VEGF, in the microenvironment of the subgranular zone (SGZ) are prime contributors to the reduced neurogenic potential. The decline in dentate neurogenesis can be observed as early as middle age. In the aged and AD brain, both the pool of neural stem cells and their proliferative potential are markedly diminished. In parallel, the level of potential regenerative factors is diminished in the brains of Alzheimer's patients compared to age-matched controls. Our efforts have been directed towards discovery and development of small, blood brain barrier penetrant molecules to promote endogenous proliferation of neural stem cells within the brain. These endeavors have led to the discovery that the neurosteroid alloprognanolone (APalpha) is a potent and highly efficacious proliferative agent in vitro and in vivo of both rodent and human neural stem cells. Results of our in vitro studies coupled with our more recent analyses in the triple transgenic mouse model of AD suggest that APalpha is a promising strategy for promoting neurogenesis in the aged brain and potentially for restoration of neuronal populations in brains recovering from neurodegenerative disease or injury. A brief overview of issues impacting the therapeutic potential of neurogenesis and the factors used to promote neurogenesis in the aging and degenerating brain is presented. Also included is a review of our current research into the neurogenic potential of the small molecule, blood brain barrier penetrating, neurosteroid allopregnanolone (APalpha).
PMID: 16842093 [PubMed - indexed for MEDLINE]
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Anthony H. Risser | neuroscience | neuropsychology | brain
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Neuroscience
Abstract of the Day: Alzheimer Disease Drug Treatments
Brinton RD & Wang JM (2006). Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res., 3(3), 185-190.
Department of Molecular Pharmacology and Toxicology and Program in Neuroscience, Pharmaceutical Science Center, 1985 Zonal Avenue, University of Southern California, Los Angeles, CA 90033, USA.
A major challenge not yet addressed by current therapeutic interventions for Alzheimer's disease (AD) is the regeneration of lost neurons and neural circuitry to restore cognitive function. Therapies that lead to cessation of the degenerative process still leave the brain riddled with deteriorated neural circuits and reduced neuron number. The discovery of neurogenesis in the adult brain and the regenerative potential of neural stem cells holds the promise for restoration of neural populations and regeneration of neural circuits necessary for cerebral function. While the regenerative potential of neural stem cells is great, so too is the challenge of delivering neural stem cells to the brain. Basic science analyses and human trials indicate that constituents of microenvironments within the brain determine the neurogenic potential, phenotypic differentiation of neural stem cells and magnitude of the neural stem cell pool. Multiple analyses have documented that dentate neurogenesis is regulated by multiple growth factors which are abundant during development and which dramatically decline with age. While the cause(s) of age-associated decline in neurogenesis remains to be fully determined, loss in growth factors, FGF-2, IGF-1 and VEGF, in the microenvironment of the subgranular zone (SGZ) are prime contributors to the reduced neurogenic potential. The decline in dentate neurogenesis can be observed as early as middle age. In the aged and AD brain, both the pool of neural stem cells and their proliferative potential are markedly diminished. In parallel, the level of potential regenerative factors is diminished in the brains of Alzheimer's patients compared to age-matched controls. Our efforts have been directed towards discovery and development of small, blood brain barrier penetrant molecules to promote endogenous proliferation of neural stem cells within the brain. These endeavors have led to the discovery that the neurosteroid alloprognanolone (APalpha) is a potent and highly efficacious proliferative agent in vitro and in vivo of both rodent and human neural stem cells. Results of our in vitro studies coupled with our more recent analyses in the triple transgenic mouse model of AD suggest that APalpha is a promising strategy for promoting neurogenesis in the aged brain and potentially for restoration of neuronal populations in brains recovering from neurodegenerative disease or injury. A brief overview of issues impacting the therapeutic potential of neurogenesis and the factors used to promote neurogenesis in the aging and degenerating brain is presented. Also included is a review of our current research into the neurogenic potential of the small molecule, blood brain barrier penetrating, neurosteroid allopregnanolone (APalpha).
PMID: 16842093 [PubMed - indexed for MEDLINE]
-
Anthony H. Risser | neuroscience | neuropsychology | brain
- Prozac And Progenitor Cells
OR, Is Hippocampal Neurogenesis Really Responsible for Antidepressant Treatment Response? [Maybe it's just a convenient marker of neural plasticity...] The Neurocritic has wondered why hippocampal neurogenesis has been touted as THE therapeutic...
- Stem-cell Research: Batten Disease
From sfgate.com:Trials for stem-cell treatment of brain disease Clinical testing set to begin on kids with fatal affliction Cornelia Stolze, Carl T. Hall, Chronicle Staff Writers San Francisco Chronicle Friday, October 21, 2005 Researchers in California...
- Human Embryonic Stem Cell Research: Pure Nerve Stem Cells
From the BBC:Scientists make nerve stem cells The world's first pure nerve stem cells made from human embryonic stem cells has been created by scientists at the University of Edinburgh. Tuesday, 16 August 2005, 07:15 GMT 08:15 UK It...
- Growing Neurons From Stem Cells In The Lab
A Reuters report, published in a number of different sources, including Wired News:Stem Cells Get Brainy By Reuters 04:04 PM Jun. 13, 2005 PT WASHINGTON -- Scientists working in mice said they had found a way to identify master cells in the brain...
- Olfactory Bulb Stem Cell Transplants And Als
A number of news reports are beginning to be published from presentations at Neuroscience 2004, the ongoing conference of the Society for Neuroscience. Here is one press release from Johns Hopkins Medical Institutions concerning a presentation about amyotrophic...