Beneficial effects of mood stabilizers lithium, valproate and lamotrigine in experimental stroke models

Wang, Zhifei; Fessler, Emily; Chuang, De‐Maw

doi:10.1038/aps.2011.140

Cited by 41 publications

(26 citation statements)

References 132 publications

(175 reference statements)

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“…Some studies investigated the post-stroke mortality among patients with schizophrenia, and the results were controversial [10], [32], [33]. Some studies found that lithium, valproate and lamotrigine, all of which are mood stabilizers used to treat bipolar disorder, had broad neuroprotective properties and may therefore be promising therapeutic agents for the treatment of neurodegenerative diseases, including stroke [34], [35], [36]. However, we found that the incidence and mortality of stroke were higher among patients with bipolar disorder than among matched controls.…”

Section: Discussionmentioning

confidence: 99%

The Incidence and Relative Risk of Stroke among Patients with Bipolar Disorder: A Seven-Year Follow-Up Study

Chou

Tsai

et al. 2013

PLoS ONE

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ObjectiveThis study aimed to estimate the incidence and relative risk of stroke and post-stroke all-cause mortality among patients with bipolar disorder.MethodsThis study identified a study population from the National Health Insurance Research Database (NHIRD) between 1999 and 2003 that included 16,821 patients with bipolar disorder and 67,284 age- and sex-matched control participants without bipolar disorder. The participants who had experienced a stroke between 1999 and 2003 were excluded and were randomly selected from the NHIRD. The incidence of stroke (ICD-9-CM code 430–438) and patient survival after stroke were calculated for both groups using data from the NIHRD between 2004 and 2010. A Cox proportional-hazards model was used to compare the seven-year stroke-free survival rate and all-cause mortality rate across the two cohorts after adjusting for confounding risk factors.ResultsA total of 472 (2.81%) patients with bipolar disorder and 1,443 (2.14%) controls had strokes over seven years. Patients with bipolar disorder were 1.24 times more likely to have a stroke (95% CI = 1.12–1.38; p<0.0001) after adjusting for demographic characteristics and comorbid medical conditions. In addition, 513 (26.8%) patients who had a stroke died during the follow-up period. The all-cause mortality hazard ratio for patients with bipolar disorder was 1.28 (95% CI = 1.06–1.55; p = 0.012) after adjusting for patient, physician and hospital variables.ConclusionsThe likelihood of developing a stroke was greater among patients with bipolar disorder than controls, and the all-cause mortality rate was higher among patients with bipolar disorder than controls during a seven-year follow-up period.

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Section: Discussionmentioning

confidence: 99%

The Incidence and Relative Risk of Stroke among Patients with Bipolar Disorder: A Seven-Year Follow-Up Study

Chou

Tsai

et al. 2013

PLoS ONE

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“…Accumulating evidence demonstrates that lithium and VPA exert beneficial effects throughout this pathophysiological process (for a review, see Chuang et al, 2009Chuang et al, , 2011Wang et al, 2011b) and hold clinical potential for its treatment.…”

Section: A Strokementioning

confidence: 99%

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

et al. 2013

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“…Studies have shown that VPA has protective properties in cellular and animal models of neurodegenerative diseases, including stroke. 14–15 We have recently demonstrated that post-ischemic VPA treatment markedly attenuates blood-brain barrier (BBB) disruption and brain edema in a rat model of middle cerebral artery occlusion (MCAO), and this protection persists at least three days after ischemia. 16 However, the effects of VPA on later-phase recovery remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Chronic Valproate Treatment Enhances Postischemic Angiogenesis and Promotes Functional Recovery in a Rat Model of Ischemic Stroke

Wang

Tsai

Munasinghe

et al. 2012

Stroke

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Background and Purpose Enhanced angiogenesis facilitates neurovascular remodeling processes and promotes brain functional recovery after stroke. Previous studies from our laboratory demonstrated that valproate (VPA), a histone deacetylase (HDAC) inhibitor, protects against experimental brain ischemia. The present study investigated whether VPA could enhance angiogenesis and promote long-term functional recovery after ischemic stroke. Methods Male rats underwent middle cerebral artery occlusion (MCAO) for 60 minutes followed by reperfusion for up to 14 days. Assessed parameters were: locomotor function via rotarod test; infarct volume via T2-weighted magnetic resonance imaging; microvessel density via immunohistochemistry; relative cerebral blood flow (rCBF) via perfusion-weighted imaging; protein levels of pro-angiogenic factors via Western blotting; and matrix metalloproteinase (MMP)-2/9 activities via gelatin zymography. Results Post-ischemic VPA treatment robustly improved the rotarod performance of MCAO rats on days 7 and 14 after ischemia, and significantly reduced brain infarction on day 14. Concurrently, VPA markedly enhanced microvessel density, facilitated endothelial cell proliferation, and increased rCBF in the ipsilateral cortex. The transcription factor hypoxia-inducible factor (HIF)-1α and its downstream pro-angiogenic factors, vascular endothelial growth factor (VEGF) and MMP-2/9, were upregulated after MCAO and significantly potentiated by VPA in the ipsilateral cortex. Acetylation of histone-H3 and H4 was robustly increased by chronic VPA treatment. The beneficial effects of VPA on rotarod performance and microvessel density were abolished by HIF-1α inhibition. Conclusions Chronic VPA treatment enhances angiogenesis and promotes functional recovery after brain ischemia. These effects may involve HDAC inhibition and upregulation of HIF-1α and its downstream pro-angiogenic factors VEGF and MMP-2/9.

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Beneficial effects of mood stabilizers lithium, valproate and lamotrigine in experimental stroke models

Cited by 41 publications

References 132 publications

The Incidence and Relative Risk of Stroke among Patients with Bipolar Disorder: A Seven-Year Follow-Up Study

The Incidence and Relative Risk of Stroke among Patients with Bipolar Disorder: A Seven-Year Follow-Up Study

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

Chronic Valproate Treatment Enhances Postischemic Angiogenesis and Promotes Functional Recovery in a Rat Model of Ischemic Stroke

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