Document Detail


Antiplatelet activity of valproic acid contributes to decreased soluble CD40 ligand production in HIV type 1-infected individuals.
MedLine Citation:
PMID:  21115729     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CD40L is a type II membrane glycoprotein of the TNF family that is found on activated T cells, B cells, and platelets. We previously reported that the soluble form of this inflammatory mediator (sCD40L) is elevated in the plasma and cerebrospinal fluid of HIV-1-infected, cognitively impaired individuals. In this study, we demonstrate that the mood-stabilizing drug valproic acid (VPA) reduces sCD40L levels in plasma samples of HIV-1-infected patients (n = 23) and in washed human platelets, which are the main source of circulating sCD40L. VPA also inhibited HIV-1 transactivator of transcription-induced release of sCD40L and platelet factor 4 in C57BL/6 mice. The mechanism by which VPA was able to do so was investigated, and we demonstrate that VPA, a known glycogen synthase kinase 3β inhibitor, blocks platelet activating factor-induced activation of glycogen synthase kinase 3β in platelets in a manner that alters sCD40L release from platelets. These data reveal that VPA has antiplatelet activity, and they convey important implications for the potential of VPA as an adjunct therapy not only for cognitively impaired patients with HIV-1 infection, but also numerous inflammatory diseases for which such antiplatelet therapies are currently lacking.
Authors:
Donna C Davidson; Michael P Hirschman; Sherry L Spinelli; Craig N Morrell; Giovanni Schifitto; Richard P Phipps; Sanjay B Maggirwar
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-11-29
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  186     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-21     Completed Date:  2011-01-27     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  584-91     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
AIDS Dementia Complex / blood,  immunology,  therapy
Animals
Blood Platelets / drug effects,  enzymology,  immunology*
CD40 Ligand / antagonists & inhibitors*,  biosynthesis*,  blood
Down-Regulation / drug effects,  immunology*
Female
Glycogen Synthase Kinase 3 / antagonists & inhibitors,  biosynthesis,  blood
HIV Infections / blood,  immunology*,  therapy
HIV-1 / drug effects,  immunology*
Humans
Inflammation Mediators / blood,  physiology,  therapeutic use
Male
Mice
Mice, Inbred C57BL
Pilot Projects
Platelet Aggregation Inhibitors / blood,  pharmacology*,  therapeutic use
Solubility
Valproic Acid / blood,  pharmacology*,  therapeutic use
Grant Support
ID/Acronym/Agency:
ES01247/ES/NIEHS NIH HHS; HL-RC1-100051/HL/NHLBI NIH HHS; HL095467/HL/NHLBI NIH HHS; R01 HL093179/HL/NHLBI NIH HHS; R01 HL093179/HL/NHLBI NIH HHS; R01 HL093179-02S109/HL/NHLBI NIH HHS; R01 HL093179-04/HL/NHLBI NIH HHS; R01 HL094547/HL/NHLBI NIH HHS; R01 NS054578/NS/NINDS NIH HHS; R01 NS054578/NS/NINDS NIH HHS; R01 NS054578-05/NS/NINDS NIH HHS; R01 NS066801/NS/NINDS NIH HHS; R01 NS066801/NS/NINDS NIH HHS; R01 NS066801-02/NS/NINDS NIH HHS; R01 NS066801-03/NS/NINDS NIH HHS; RC1 HL100051/HL/NHLBI NIH HHS; RC1 HL100051-02/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Inflammation Mediators; 0/Platelet Aggregation Inhibitors; 147205-72-9/CD40 Ligand; 614OI1Z5WI/Valproic Acid; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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