title: Potent neuroprotective effects of novel structural derivatives of valproic acid: potential roles of HDAC inhibition and HSP70 induction.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.forename: Zoya
authors.initials: Z
authors.lastname: Marinova
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Reis-Fernandes
authors.forename: Heinz
authors.initials: H
authors.lastname: Nau
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
mesh_terms: 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*
chemical_list: 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
references.citation: Mol Pharmacol. 2005 May;67(5):1426-33
references.pmid: 15687223
references.citation: Chem Res Toxicol. 2006 Feb;19(2):272-8
references.pmid: 16485903
references.citation: Neuropharmacology. 2007 Mar;52(3):764-78
references.pmid: 17095022
references.citation: EMBO J. 2001 Dec 17;20(24):6969-78
references.pmid: 11742974
references.citation: Mol Psychiatry. 2009 Jan;14(1):51-9
references.pmid: 17925795
references.citation: Am J Hematol. 2006 May;81(5):374-6
references.pmid: 16628726
references.citation: Biol Psychiatry. 2007 Jul 1;62(1):55-64
references.pmid: 16945350
references.citation: J Neurochem. 2009 Nov;111(4):976-87
references.pmid: 19765194
references.citation: Arch Dis Child. 2002 Dec;87(6):462-6
references.pmid: 12456539
references.citation: Drug Metab Dispos. 2006 Apr;34(4):612-20
references.pmid: 16415118
references.citation: Trends Neurosci. 2009 Nov;32(11):591-601
references.pmid: 19775759
references.citation: Med Res Rev. 2005 Jul;25(4):383-97
references.pmid: 15637697
references.citation: Mol Psychiatry. 2006 Dec;11(12):1116-25
references.pmid: 16969367
references.citation: J Neurosci. 2008 Mar 5;28(10):2576-88
references.pmid: 18322101
references.citation: J Neurosci. 2006 Jul 12;26(28):7502-12
references.pmid: 16837598
references.citation: J Biol Chem. 2001 Sep 28;276(39):36734-41
references.pmid: 11473107
references.citation: J Chromatogr. 1981 Nov 13;226(1):69-78
references.pmid: 6798056
references.citation: J Neurochem. 2004 Jun;89(6):1358-67
references.pmid: 15189338