Valproic acid stimulates clusterin expression in human astrocytes: Implications for Alzheimer's disease

Nuutinen, Tapio; Suuronen, Tiina; Kauppinen, Anu; Salminen, Antero

doi:10.1016/j.neulet.2010.03.041

Cited by 61 publications

(42 citation statements)

References 46 publications

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“…VPA has also emerged as an anti-neoplastic agent that can influence cell growth, differentiation, and apoptosis. In addition, VPA displays a neuroprotective function in several animal models of neurodegenerative diseases (Nuutinen et al, 2010). However, recent findings suggest that all of these diverse actions of VPA may be mediated through its action as a HDAC inhibitor (Chuang et al, 2009;Monti et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

Montalvo-Ortiz

Keegan

Gallardo

et al. 2013

Neuropsychopharmacol

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Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL þ VPA and HAL þ MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.

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Section: Discussionmentioning

confidence: 99%

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

Montalvo-Ortiz

Keegan

Gallardo

et al. 2013

Neuropsychopharmacol

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“…In human astrocytes, moreover, VPA (but not lithium) has been shown to act as a potent inducer of clusterin expression and secretion (Nuutinen et al, 2010). Clusterin is a small, HSP-like molecular chaperone, in which secretion is induced by stress.…”

Section: Admentioning

confidence: 99%

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

et al. 2013

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“…40,57 As opposed to concomitant use of benzodiazepines or other anticonvulsants, the GABAergic effects of valproic acid and the dopaminergic actions of antipsychotics, when used together, may allow for lower doses of each drug. 40 At the same time, our finding that similar valproic acid serum levels were achieved regardless of whether valproic acid was monotherapy or combination therapy leads to several important questions including (1) what is the active entity or entities when valproic acid is used in conjunction with other psychotropics, (2) what psychotropics, if any, should be used with valproic acid, and (3) should clinicians target different valproic acid serum levels based solely on the monotherapy status of valproic acid? Controlled trials of valproic acid as adjunctive or combination therapy in patients with dementia are needed.…”

Section: Clinical and Research Implicationsmentioning

confidence: 99%

“…1 In vitro and in vivo studies have demonstrated that valproic acid may have neuroprotective effects on Alzheimer's disease (AD) via numerous potential mechanisms such as prevention of betaamyloid aggregation, decreased beta-amyloid and neuritic plaque production, and induction of neurogenesis. [2][3][4] At the same time, evidence-based treatment guidelines and position statements for dementia do not generally recommend anticonvulsants but state that their use can be considered in some patients. 5,6 This leaves clinicians with few appealing options when faced with the need to pharmacologically intervene in patients with behavioral disturbances in dementia.…”

Section: Introductionmentioning

confidence: 99%

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Valproic Acid in Dementia

Dolder

Nealy

McKinsey

2011

Journal of Pharmacy Practice

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Valproic acid is widely used in the treatment of behavioral disturbances in patients with dementia; however, there is uncertainty about its dosing and studies have reported mixed findings. The current article examines published trials of valproic acid in the treatment of patients with dementia to identify whether an optimal dosing strategy exists. Secondarily, valproic acid dosing from published studies is compared with a real-world 5-year sample of valproic acid prescribing. Twenty studies met selection criteria and were included in the review. Based primarily on uncontrolled trials and the current retrospective study, valproic acid serum levels between 40 and 60 mcg/mL and relatively low doses (ie, 7-12 mg/kg per d) are associated with improvements in agitation in some patients with dementia. At the same time, similar valproic acid levels produced no significant behavioral improvements in most placebo-controlled studies and led to substantial side effects in some patients. Considerable trial design differences exist between controlled and uncontrolled trials. Overall, valproic acid appears to have limited efficacy as monotherapy in many patients with dementia. Its optimal role may be in combination with other psychotropics as a treatment of agitation associated with dementia.

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Valproic acid stimulates clusterin expression in human astrocytes: Implications for Alzheimer's disease

Cited by 61 publications

References 46 publications

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

Valproic Acid in Dementia

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