Document Detail


Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking.
MedLine Citation:
PMID:  21964384     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Clavulanic acid is a CNS-modulating compound with exceptional blood-brain barrier permeability and safety profile. Clavulanic acid has been proposed to have anti-depressant activity and is currently entering Phase IIb clinical trials for the treatment of Major Depressive Disorder (MDD). Studies have also shown that clavulanic acid suppresses anxiety and enhances sexual functions in rodent and primate models by a mechanism involving central nervous system (CNS) modulation, although its detailed mechanism of action has yet to be elucidated. To further examine its potential as a CNS modulating agent as well as its mechanism of action, we investigated the effects of clavulanic acid in neuronal cells. Our results indicate that clavulanic acid enhances dopamine release in PC12 and SH-SY5Y cells without affecting dopamine synthesis. Furthermore, using affinity chromatography we were able to identify two proteins, Munc18-1 and Rab4 that potentially bind to clavulanic acid and play a critical role in neurosecretion and the vesicle trafficking process. Consistent with this result, an increase in the translocation of Munc18-1 and Rab4 from the cytoplasm to the plasma membrane was observed in clavulanic acid treated cells. Overall, these data suggest that clavulanic acid enhances dopamine release in a mechanism involving Munc18-1 and Rab4 modulation and warrants further investigation of its therapeutic use in CNS disorders, such as depression.
Authors:
Gina Chun Kost; Senthil Selvaraj; Young Bok Lee; Deog Joong Kim; Chang-Ho Ahn; Brij B Singh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-09-21
Journal Detail:
Title:  Neuroscience letters     Volume:  504     ISSN:  1872-7972     ISO Abbreviation:  Neurosci. Lett.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-17     Completed Date:  2012-02-07     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  7600130     Medline TA:  Neurosci Lett     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  170-5     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Bacterial Agents / pharmacology*
Blood-Brain Barrier / drug effects
Cell Line
Cell Line, Tumor
Cell Membrane / metabolism
Clavulanic Acid / pharmacology*
Cytoplasm / metabolism
Dopamine / metabolism*
Exocytosis / drug effects
Fluorescent Antibody Technique
Humans
Munc18 Proteins / metabolism
Neurons / drug effects,  metabolism*
PC12 Cells
Protein Binding
Rats
Synaptic Vesicles / drug effects,  metabolism*
rab GTP-Binding Proteins / metabolism
Grant Support
ID/Acronym/Agency:
5P20RR017699/RR/NCRR NIH HHS; DE017102/DE/NIDCR NIH HHS; R01 DE017102/DE/NIDCR NIH HHS; R01 DE017102-01A1/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Munc18 Proteins; 23521W1S24/Clavulanic Acid; EC 3.6.1.-/rab GTP-Binding Proteins; VTD58H1Z2X/Dopamine
Comments/Corrections

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