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Neurotrophic and Neuroprotective Actions of (−)- and (+)-Phenserine, Candidate Drugs for Alzheimer’s Disease
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 expe...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559887/ https://www.ncbi.nlm.nih.gov/pubmed/23382994 http://dx.doi.org/10.1371/journal.pone.0054887 |
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author | Lilja, Anna M. Luo, Yu Yu, Qian-sheng Röjdner, Jennie Li, Yazhou Marini, Ann M. Marutle, Amelia Nordberg, Agneta Greig, Nigel H. |
author_facet | Lilja, Anna M. Luo, Yu Yu, Qian-sheng Röjdner, Jennie Li, Yazhou Marini, Ann M. Marutle, Amelia Nordberg, Agneta Greig, Nigel H. |
author_sort | Lilja, Anna M. |
collection | PubMed |
description | 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). |
format | Online Article Text |
id | pubmed-3559887 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35598872013-02-04 Neurotrophic and Neuroprotective Actions of (−)- and (+)-Phenserine, Candidate Drugs for Alzheimer’s Disease Lilja, Anna M. Luo, Yu Yu, Qian-sheng Röjdner, Jennie Li, Yazhou Marini, Ann M. Marutle, Amelia Nordberg, Agneta Greig, Nigel H. PLoS One Research Article 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). Public Library of Science 2013-01-30 /pmc/articles/PMC3559887/ /pubmed/23382994 http://dx.doi.org/10.1371/journal.pone.0054887 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Lilja, Anna M. Luo, Yu Yu, Qian-sheng Röjdner, Jennie Li, Yazhou Marini, Ann M. Marutle, Amelia Nordberg, Agneta Greig, Nigel H. Neurotrophic and Neuroprotective Actions of (−)- and (+)-Phenserine, Candidate Drugs for Alzheimer’s Disease |
title | Neurotrophic and Neuroprotective Actions of (−)- and (+)-Phenserine, Candidate Drugs for Alzheimer’s Disease |
title_full | Neurotrophic and Neuroprotective Actions of (−)- and (+)-Phenserine, Candidate Drugs for Alzheimer’s Disease |
title_fullStr | Neurotrophic and Neuroprotective Actions of (−)- and (+)-Phenserine, Candidate Drugs for Alzheimer’s Disease |
title_full_unstemmed | Neurotrophic and Neuroprotective Actions of (−)- and (+)-Phenserine, Candidate Drugs for Alzheimer’s Disease |
title_short | Neurotrophic and Neuroprotective Actions of (−)- and (+)-Phenserine, Candidate Drugs for Alzheimer’s Disease |
title_sort | neurotrophic and neuroprotective actions of (−)- and (+)-phenserine, candidate drugs for alzheimer’s disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559887/ https://www.ncbi.nlm.nih.gov/pubmed/23382994 http://dx.doi.org/10.1371/journal.pone.0054887 |
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