Valproic acid induces microglial dysfunction, not apoptosis, in human glial cultures.
Valproic acid (VPA) is widely used for the treatment of mood disorders and epilepsy, but its mechanism of action is unclear. In vivo and in vitro studies using rodent models have demonstrated that VPA has both neuroprotective and neurotrophic effects. These beneficial effects are, in part, through modulation of glial cell function. Recently, we and others have shown that VPA selectively induces caspase-3 mediated apoptosis in rodent microglial cells. However, the effect of VPA on human microglia has not been tested. In this study, using microglia derived from adult human brains, we demonstrate that VPA does not induce microglial apoptosis as determined by the absence of caspase-3 cleavage. However, VPA does partially decrease the expression of the microglial markers PU.1 and CD45, as well as dramatically reducing microglial phagocytosis. Due to the many roles of microglia in the brain, these VPA-induced alterations in microglial phenotype could potentially have major effects on physiological and pathological actions of these cells.
Gibbons
Hannah M
HM
Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand.
Smith
Amy M
AM
Teoh
H Heng
HH
Bergin
Peter M
PM
Mee
Edward W
EW
Faull
Richard L M
RL
Dragunow
Mike
M
D000328:Adult; D000927:Anticonvulsants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D017493:Leukocyte Common Antigens / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014635:Valproic Acid / Q000633:toxicity*; D000099232:Proto-Oncogene Protein Spi-1
D000927:Anticonvulsants; D053148:Caspase 3; D017493:Leukocyte Common Antigens; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014635:Valproic Acid; D000099232:Proto-Oncogene Protein Spi-1; C516769:PTPRC protein, human