A positively charged α-lipoic acid analogue with increased cellular uptake and more potent immunomodulatory activity

Chandan K. Sen*, Oren Tirosh, Sashwati Roy, Michael S. Kobayashi, Lester Packer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

α-Lipoic acid (LA) is taken up by cells and reduced to its potent dithiol form, dihydrolipoate(DHLA), much of which is rapidly effluxed out from cells. To improve retention in cells, the LA molecule was modified to confer a positive charge at physiological pH. N,N-dimethyl, N'-2-amidoethyl-lipoate was synthesized. The protonated form of the new molecule is referred to as LA-Plus. The uptake of LA-Plus by human Wurzburg T cells was higher compared to that of LA. Several-fold higher amounts of DHLA-Plus, the corresponding reduced form of LA-Plus, were detected in LA-Plus treated cells compared to the amount of DHLA found in cells treated with LA. At 100 μM, LA did not but LA-Plus inhibited H2O2 induced NF-κB activation and NF-κB directed IL-2 receptor expression. Both LA and LA-Plus synergised with selenium in inhibiting H2O2 induced NF-κB activation. At 150 μM LA-Plus, but not LA, inhibited TNFα induced NF-κB activation. At 5 μM LA-Plus, but not LA, protected against both spontaneous and etoposide induced apoptosis in rat thymocytes. LA-Plus is thus an improved form of LA with increased therapeutic potential.

Original languageAmerican English
Pages (from-to)223-228
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume247
Issue number2
DOIs
StatePublished - 18 Jun 1998
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health Grant DK 50430 and a gift to the Regents of the University of California. C.K.S. and O.T. contributed equally to this work.

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