Designer drugs are the trend these days, but what of the classics? In the category of well-known medicines that don’t go out of style, consider valproic acid. This short-chain fatty acid came to market in the United States in 1983 to treat seizure disorders and found frequent off-label use as a mood stabilizer. Now this cheap and widely used compound is being retailored as a possible neuroprotective agent for Alzheimer disease (AD).
That effort may get a boost from a new study looking at valproic acid for dementia in HIV-infected people. In a small, placebo-controlled pilot trial, Giovanni Schifitto, Harris Gelbard, and colleagues at the University of Rochester Medical Center, New York, and the University of Nebraska Medical Center in Omaha report a trend toward improved cognitive performance and normalization of brain metabolism after valproate treatment of impaired, HIV-positive subjects. The results, appearing online this month in Neurology, may give hope to researchers who are midway through a larger trial to look at valproic acid in Alzheimer disease (see below).
The HIV trial enrolled 22 people, six without and 16 with cognitive impairment, who took 250 mg of valproic acid or placebo twice daily for 10 weeks. They were evaluated with neuropsychological tests and by magnetic resonance spectroscopy (MRS), which measured markers of neuronal metabolism in the brain. The treatment was well tolerated, and did not affect levels of HIV RNA or CD4 T cells.
Over the course of treatment, there were no statistically significant changes in any given cognitive measure, but the treated patients tended to show a better performance overall. MRS revealed that treatment resulted in a significant increase in the N-acetyl aspartate to creatine ratio in frontal white matter. (A decrease in the NAA/Cr ratio has been previously observed in HIV-infected people compared to non-infected controls, and may be a marker for neuronal dysfunction or death.)
In AD, valproate has been investigated for the treatment of agitation and aggressive behavior, with variable results in four placebo-controlled trials. An additional open-label study is ongoing to look for behavioral effects of the drug (see more at clinicaltrials.gov).
To assess the potential neuroprotective effects of valproate, the Alzheimer’s Disease Cooperative Study (ADCS) is recruiting patients for a Phase 3 trial that asks a slightly different question. The multicenter trial, led by Pierre Tariot, now at Banner Alzheimer's Institute in Phoenix, Arizona, aims to enroll 300 AD patients who do not display agitation or psychosis to determine if treatment can delay the development of those behaviors (see more information at clinicaltrials.gov). The study will also track disease progression with cognitive and functional measures. Tariot and coworkers recently published the results of a pilot dosing trial for the study (Profenno et al., 2005).
How might valproate work to protect neurons? The compound inhibits GSK3β activation by apoptotic stimuli. In viral infection or AD, valproate may reduce ER stress caused by misfolded proteins and promote cell survival (Kim et al., 2005). Inhibition of GSK3β could also reduce phospho-tau pathology, leading to a protective effect on neurons. Treatment with HIV protease cocktails, as well as intractable epilepsy, both lead to amyloid pathology (Achim et al., 2005 and Gouras et al. 1997), and perhaps valproate intervenes to prevent that. One report shows that valproate enhances neurogenesis in rats (Hao et al., 2004). Even this old faithful apparently still carries some secrets up its sleeve.—Pat McCaffrey
- Profenno LA, Jakimovich L, Holt CJ, Porsteinsson A, Tariot PN. A randomized, double-blind, placebo-controlled pilot trial of safety and tolerability of two doses of divalproex sodium in outpatients with probable Alzheimer's disease. Curr Alzheimer Res. 2005 Dec;2(5):553-8. PubMed.
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- Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL. Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS. 2005 Mar 4;19(4):407-11. PubMed.
- Gouras GK, Relkin NR, Sweeney D, Munoz DG, Mackenzie IR, Gandy S. Increased apolipoprotein E epsilon 4 in epilepsy with senile plaques. Ann Neurol. 1997 Mar;41(3):402-4. PubMed.
- Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci. 2004 Jul 21;24(29):6590-9. PubMed.
- Loy R, Tariot PN. Neuroprotective properties of valproate: potential benefit for AD and tauopathies. J Mol Neurosci. 2002 Dec;19(3):303-7. PubMed.
- Schifitto G, Peterson DR, Zhong J, Ni H, Cruttenden K, Gaugh M, Gendelman HE, Boska M, Gelbard H. Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report. Neurology. 2006 Mar 28;66(6):919-21. PubMed.