Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease.

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).

• Authors: Anna M Lilja, Yu Luo, Qian-sheng Yu, Jennie Röjdner, Yazhou Li, Ann M Marini, Amelia Marutle, Agneta Nordberg, Nigel H Greig
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e54887 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23382994 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Dcx protein, mouse
• Doublecortin Protein
• Neuroprotective Agents
• Peptide Fragments
• amyloid beta-protein (1-42)
• Physostigmine
• phenserine

Topics

• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (pharmacology)
• Amyloid beta-Protein Precursor (genetics, 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, drug effects, metabolism)
• Neurons (cytology, drug effects, metabolism)
• Neuroprotective Agents (chemistry, pharmacology, therapeutic use)
• Oxidative Stress (drug effects)
• Peptide Fragments (pharmacology)
• Physostigmine (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Stereoisomerism