Antiplatelet activity of valproic acid contributes to decreased soluble CD40 ligand production in HIV type 1-infected individuals.
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.
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Donna C
DC
Davidson
Michael P
MP
Hirschman
Sherry L
SL
Spinelli
Craig N
CN
Morrell
Giovanni
G
Schifitto
Richard P
RP
Phipps
Sanjay B
SB
Maggirwar
D015526:AIDS Dementia Complex / Q000097:blood / Q000276:immunology / Q000628:therapy; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000097:blood; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D000071679:Glycogen Synthase Kinase 3 beta; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000628:therapy; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000502:physiology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010865:Pilot Projects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D012995:Solubility; D014635:Valproic Acid / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
D018836:Inflammation Mediators; D010975:Platelet Aggregation Inhibitors; D023201:CD40 Ligand; D014635:Valproic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3