Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking

Gina Chun Kost, Senthil Selvaraj, Young Bok Lee, Deog Joong Kim, Chang Ho Ahn, Brij B. Singh

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)170-175
Number of pages6
JournalNeuroscience Letters
Volume504
Issue number2
DOIs
Publication statusPublished - 24 Oct 2011

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Keywords

  • Clavulanic acid
  • Depression
  • Dopamine
  • Neurotransmitter release
  • Rab4/Munc18-1

ASJC Scopus subject areas

  • Neuroscience(all)

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