Potent neuroprotective effects of novel structural derivatives of valproic acid: potential roles of HDAC inhibition and HSP70 induction.
Emerging evidence suggests that the neuroprotective effects of valproic acid (VPA) occur via inhibition of histone deacetylases (HDACs) and activation of gene expression. This study assessed the ability of four VPA derivatives to cause histone hyperacetylation and protect against glutamate-induced excitotoxicity in cultured neurons. We found that (S)-2-pentyl-4-pentynoic acid (compound III) and (+/-)-2-hexyl-4-pentynoic acid (compound V) were far more potent and robust than VPA in inducing histone hyperacetylation and protecting against glutamate excitotoxicity. Thus, the increase in histone acetylation elicited by compounds III and V was significant at 5microM and reached a maximal increase of 600-700% at 50-100microM, compared with only a 200% increase by VPA at 100microM. The neuroprotective effects of compounds III and V were evident at 10-25microM and reached a complete protection at 50-100microM, while a significant partial protection by VPA was observed at 100microM. These two compounds were also more effective than VPA in increasing HSP70-1a and HSP70-1b mRNA levels. At 50microM, compound V was most robust in increasing HSP-1a mRNA levels, followed by compound III, and then by VPA. HSP-1b mRNA was only significantly upregulated by compounds V and III, but not by VPA or other VPA derivatives under these treatment conditions. Our results suggest that these two VPA derivatives may ultimately be developed into potent neuroprotective drugs in preclinical and clinical studies.
Leng
Yan
Y
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bldg. 10, Rm. 3D-38, 10 Center Dr, Bethesda, MD 20892-1363, USA.
Marinova
Zoya
Z
Reis-Fernandes
Marcos A
MA
Nau
Heinz
H
Chuang
De-Maw
DM
D000107:Acetylation; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
C551394:2-hexyl-4-pentynoic acid; C551393:2-pentyl-4-pentynoic acid; D005231:Fatty Acids, Unsaturated; D050884:HSP72 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D018698:Glutamic Acid; D014635:Valproic Acid
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