Neuroprotective effects and mechanism of cognitive-enhancing choline analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture and Caenorhabditis elegans

Hdl Handle:
http://hdl.handle.net/10675.2/622
Title:
Neuroprotective effects and mechanism of cognitive-enhancing choline analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture and Caenorhabditis elegans
Authors:
Keowkase, Roongpetch; Aboukhatwa, Marwa; Adam, Bao-Ling; Beach, J Warren; Terry, Alvin V.; Buccafusco, Jerry J; Luo, Yuan
Abstract:
Background: Our previous work indicated that novel analogs of choline have cytoprotective effects in vitro that might be useful in neurodegenerative conditions such as Alzheimer's disease (AD). Furthermore, two lead compounds (JWB1-84-1 and JAY2-22-33) from a library of more than 50 improved cognitive performances in a transgenic mouse model of AD. The purpose of these experiments was to more specifically investigate the neuroprotective capabilities of these lead compounds both in vitro and in vivo.; Results: We used N2a cells which express a Swedish mutation in the amyloid precursor protein and presenilin 1 genes to investigate the effect of JWB1-84-1 and JAY2-22-33 on b-amyloid (Ab) levels and found that both compounds significantly reduced Ab levels. JWB1-84-1 and JAY2-22-33 also protected rat primary cortical neurons from Ab toxicity. Subsequently, we utilized the nematode Caenorhabditis elegans (C. elegans) as an in vivo model organism to identify potential molecular targets of these compounds. In the C. elegans model of Ab toxicity, human Ab is expressed intracellularly in the body wall muscle. The expression and subsequent aggregation of Ab in the muscle leads to progressive paralysis.; Conclusion: We found that JAY2-22-33 (but not JWB1-84-1) significantly reduced Ab toxicity by delaying paralysis and this protective effect required both the insulin signaling pathway and nicotinic acetylcholine receptors (nAChRs).
Citation:
Mol Neurodegener. 2010 Dec 16; 5:59
Issue Date:
16-Dec-2010
URI:
http://hdl.handle.net/10675.2/622
DOI:
10.1186/1750-1326-5-59
PubMed ID:
21162742
PubMed Central ID:
PMC3017027
Type:
Article
ISSN:
1750-1326
Appears in Collections:
Department of Pharmacology and Toxicology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorKeowkase, Roongpetchen_US
dc.contributor.authorAboukhatwa, Marwaen_US
dc.contributor.authorAdam, Bao-Lingen_US
dc.contributor.authorBeach, J Warrenen_US
dc.contributor.authorTerry, Alvin V.en_US
dc.contributor.authorBuccafusco, Jerry Jen_US
dc.contributor.authorLuo, Yuanen_US
dc.date.accessioned2012-10-26T16:26:54Z-
dc.date.available2012-10-26T16:26:54Z-
dc.date.issued2010-12-16en_US
dc.identifier.citationMol Neurodegener. 2010 Dec 16; 5:59en_US
dc.identifier.issn1750-1326en_US
dc.identifier.pmid21162742en_US
dc.identifier.doi10.1186/1750-1326-5-59en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/622-
dc.description.abstractBackground: Our previous work indicated that novel analogs of choline have cytoprotective effects in vitro that might be useful in neurodegenerative conditions such as Alzheimer's disease (AD). Furthermore, two lead compounds (JWB1-84-1 and JAY2-22-33) from a library of more than 50 improved cognitive performances in a transgenic mouse model of AD. The purpose of these experiments was to more specifically investigate the neuroprotective capabilities of these lead compounds both in vitro and in vivo.en_US
dc.description.abstractResults: We used N2a cells which express a Swedish mutation in the amyloid precursor protein and presenilin 1 genes to investigate the effect of JWB1-84-1 and JAY2-22-33 on b-amyloid (Ab) levels and found that both compounds significantly reduced Ab levels. JWB1-84-1 and JAY2-22-33 also protected rat primary cortical neurons from Ab toxicity. Subsequently, we utilized the nematode Caenorhabditis elegans (C. elegans) as an in vivo model organism to identify potential molecular targets of these compounds. In the C. elegans model of Ab toxicity, human Ab is expressed intracellularly in the body wall muscle. The expression and subsequent aggregation of Ab in the muscle leads to progressive paralysis.en_US
dc.description.abstractConclusion: We found that JAY2-22-33 (but not JWB1-84-1) significantly reduced Ab toxicity by delaying paralysis and this protective effect required both the insulin signaling pathway and nicotinic acetylcholine receptors (nAChRs).en_US
dc.rightsCopyright ©2010 Keowkase et al; licensee BioMed Central Ltd.en_US
dc.subjectResearch Articleen_US
dc.titleNeuroprotective effects and mechanism of cognitive-enhancing choline analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture and Caenorhabditis elegansen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3017027en_US
dc.contributor.corporatenameDepartment of Pharmacology and Toxicology-

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