Journal of Molecular Neuroscience

, Volume 19, Issue 3, pp 301–307 | Cite as

Neuroprotective properties of valproate

Potential benefit for AD and tauopathies
Preclinical Proof Of Concept


Neuropsychiatric disturbances are extremely common in Alzheimer’s disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.

Index Entries

Anticonvulsants neurodegeneration Alzheimer’s disease kinase phosphorylation neurofibrillary tangles 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Chen G., Huang L. D., Jiang Y. M., and Manji H. K. (1999) The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J. Neurochem. 72, 1327–1330.PubMedCrossRefGoogle Scholar
  2. Cohen P. and Frame S. (2001) The renaissance of GSK3. Nat. Rev.: Mol. Cell Biol. 2, 769–776.CrossRefGoogle Scholar
  3. Cohen-Mansfield J. and Werner P. (1998) Longitudinal changes in behavioral problems in old age: a study in an adult day care population. J. Gerontol. A. Biol. Sci. Med. Sci. 53, M65-M71.PubMedGoogle Scholar
  4. Cummings J. L., Mega M., Gray K., Rosenberg-Thompson S., Carusi D. A., and Gornbein J. (1994) The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 44, 2308–2314.PubMedGoogle Scholar
  5. Farber N. B., Rubin E. H., Newcomer J. W., Kinscherf D. A., Miller J. P., Morris J. C., et al. (2000) Increased neocortical neurofibrillary tangle density in subjects with alzheimer disease and psychosis. Arch. Gen. Psychiatry 57, 1165–1173.PubMedCrossRefGoogle Scholar
  6. Finkel S. I., Costa, Cohen G., Miller S., and Sartorius N. (1996) Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Int. Psychogeriatr. 8(Suppl. 3), 497–500.PubMedGoogle Scholar
  7. Grimes C. A. and Jope R. S. (1999) Cholinergic stimulation of early growth response-1 DNA binding activity requires protein kinase C and mitogen-activated protein kinase kinase activation and is inhibited by sodium valproate in SH-SY5Y cells. J. Neurochem. 73, 1384–1392.PubMedCrossRefGoogle Scholar
  8. Hoshi M., Takashima A., Noguchi K., Murayama M., Sato M., Kondo S., et al. (1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc. Natl. Acad. Sci. USA 93, 2719–2723.PubMedCrossRefGoogle Scholar
  9. Imahori K. and Uchida T. (1997) Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease. J. Biochem. 121, 179–188.PubMedGoogle Scholar
  10. Imahori K., Hoshi M., Ishiguro K., Sato K., Takahashi M., Shiurba R., et al. (1998) Possible role of tau protein kinases in pathogenesis of Alzheimer’s disease. Neurobiol. Aging 19. S93-S98.PubMedCrossRefGoogle Scholar
  11. Leibovici A. and Tariot P. N. (1988) Carbamazepine treatment of agitation associated with dementia. J. Geriatr. Psychiatry Neurol. 1, 110–112.PubMedCrossRefGoogle Scholar
  12. Lyketsos C. G., Steinberg M., Tschanz J. T., Norton M. C., Steffens D. C., and Breitner J. C. (2000) Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am. J. Psychiatry 157, 708–714.PubMedCrossRefGoogle Scholar
  13. Mark R. J., Ashford J. W., Goodman Y., and Mattson M. P. (1995) Anticonvulsants attenuate amyloid beta-peptide neurotoxicity, Ca2+ deregulation, and cytoskeletal pathology. Neurobiol. Aging 16, 187–198.PubMedCrossRefGoogle Scholar
  14. Paulsen J. S., Salmon D. P., Thal L. J., Romero R., Weisstein-Jenkins C., Galasko D., et al. (2000) Incidence of and risk factors for hallucinations and delusions in patients with probable AD. Neurology 54, 1965–1971.PubMedGoogle Scholar
  15. Porsteinsson A. P., Tariot P. N., Erb R., et al. (2001) Placebo-controlled study of divalproex sodium for agitation in dementia. Am. J. Geriat. Psychiatry 9, 58–66.CrossRefGoogle Scholar
  16. Sun X., Sato S., Murayama O., et al. (2002) Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci. Lett. 321, 61–64.PubMedCrossRefGoogle Scholar
  17. Tariot P. and Blazina L. (1993) The psychopathology of dementia, in Handbook of Dementing Illnesses (Morris J., ed.), Marcel Dekker, New York, pp. 461–475.Google Scholar
  18. Tariot P. N., Schneider L. S., and Katz I. R. (1995) Anti-convulsant and other non-neuroleptic treatment of agitation in dementia. J. Geriatr. Psychiatry Neurol. 8(Suppl. 1), S28-S39.PubMedCrossRefGoogle Scholar
  19. Tariot P. N., Erb R., Podgorski C. A., Cox C., Patel S., Jakimovich L., et al. (1998) Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am. J. Psychiatry 155, 54–61.PubMedGoogle Scholar
  20. Tariot P. N., Schneider L., Mintzer J., Cutler A., Cunningham M., Thomas J., et al. (2001) Safety and tolerability of divalproex sodium for the treatment of signs and symptoms of mania in elderly patients with dementia: results of a double-blind, placebo-controlled trial. Curr. Therapeut. Res. 62, 51–67.CrossRefGoogle Scholar
  21. Tekin S., Mega M. S., Masterman D. M., Chow T., Garakian J., Vinters H. V., et al. (2001) Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann. Neurol. 49, 355–361.PubMedCrossRefGoogle Scholar
  22. Thal D. R., Holzer M., Rub U., Waldmann G., Gunzel S., Zedlick D., et al. (2000) Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Exp. Neurol. 163, 98–110.PubMedCrossRefGoogle Scholar
  23. Tong N., Sanchez J. F., Maggirwar S. B., et al. (2001) Activation of glycogen synthase kinase 3 beta (GSK-3β) by platelet activating factor mediates migration and cell death in cerebral granule neurons. Eur. J. Neurosci. 13, 1913–1922.PubMedCrossRefGoogle Scholar
  24. van Gijn M. E., Snel F., Cleutjens J. P., et al. (2001) Over-expression of components of the Frizzled-Dishevelled cascade results in apoptotic cell death, mediated by β-catenin, Exp. Cell. Res. 265, 46–53.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Rochester School of Medicine and DentistryRochester
  2. 2.Department of Psychiatry, Program in Neurobehavioral TherapeuticsUniversity of Rochester School of Medicine and DentistryRochester

Personalised recommendations