Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition.
We studied the neuroprotective effects of valproic acid (VPA), a primary mood stabilizer and anticonvulsant, in cultured rat cerebral cortical neurons (CCNs). CCNs underwent spontaneous cell death when their age increased in culture. As shown by mitochondrial activity and calcein-AM assays, treatment of CCNs with VPA starting from day 9 in vitro markedly increased viability and prolonged the life span of the cultures. The neuroprotective action of VPA was time-dependent and occurred at therapeutic levels with a maximal effect at about 0.5 mM. LiCl (1 mM) also protected CCNs from aging-induced, spontaneous cell death but less effectively. VPA-induced neuroprotection in aging CCN cultures was associated with a robust increase in histone H3 acetylation levels and the protective effect was mimicked by treatment with a histone deacetylase inhibitor, trichostatin A, but not by VPA analogs which are inactive in blocking histone deacetylase. Our results suggest a role of histone deacetylase inhibition in mediating the neuroprotective action of VPA.
Jeong
Mi Ra
MR
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bldg. 10, Rm. 4C-206, 10 Center Dr MSC 1363, Bethesda, MD 20892-1363, USA.
Hashimoto
Ryota
R
Senatorov
Vladimir V
VV
Fujimaki
Koichiro
K
Ren
Ming
M
Lee
Min Soo
MS
Chuang
De-Maw
DM
D000375:Aging; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D018692:Antimanic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D014635:Valproic Acid