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Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease.
- Source :
-
PloS one [PLoS One] 2013; Vol. 8 (1), pp. e54887. Date of Electronic Publication: 2013 Jan 30. - Publication Year :
- 2013
-
Abstract
- Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of oxidative stress, toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with the Aβ lowering AD experimental drugs (+)-phenserine and (-)-phenserine in neuronal cultures, and actions in mice were evaluated with (+)-phenserine. Both experimental drugs together with the metabolite N1-norphenserine induced neurotrophic actions in human SH-SY5Y cells that were mediated by the protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) pathways, were evident in cells expressing amyloid precursor protein Swedish mutation (APP(SWE)), and retained in the presence of Aβ and oxidative stress challenge. (+)-Phenserine, together with its (-) enantiomer as well as its N1- and N8-norphenserine and N1,N8-bisnorphenserine metabolites, likewise provided neuroprotective activity against oxidative stress and glutamate toxicity via the PKC and ERK pathways. These neurotrophic and neuroprotective actions were evident in primary cultures of subventricular zone (SVZ) neural progenitor cells, whose neurosphere size and survival were augmented by (+)-phenserine. Translation of these effects in vivo was assessed in wild type and AD APPswe transgenic (Tg2576) mice by doublecortin (DCX) immunohistochemical analysis of neurogenesis in the SVZ, which was significantly elevated by 16 day systemic (+)-phenserine treatment, in the presence of a (+)-phenserine-induced elevation in brain- derived neurotrophic factor (BDNF).
- Subjects :
- Amyloid beta-Peptides pharmacology
Amyloid beta-Protein Precursor genetics
Amyloid beta-Protein Precursor metabolism
Animals
Cell Line, Tumor
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Doublecortin Protein
Drug Discovery
Gene Expression Regulation drug effects
Humans
Mice
Mice, Transgenic
Mutation
Neural Stem Cells cytology
Neural Stem Cells drug effects
Neural Stem Cells metabolism
Neurons cytology
Neurons drug effects
Neurons metabolism
Neuroprotective Agents therapeutic use
Oxidative Stress drug effects
Peptide Fragments pharmacology
Physostigmine chemistry
Physostigmine pharmacology
Physostigmine therapeutic use
Stereoisomerism
Alzheimer Disease drug therapy
Neuroprotective Agents chemistry
Neuroprotective Agents pharmacology
Physostigmine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23382994
- Full Text :
- https://doi.org/10.1371/journal.pone.0054887