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

Wang, Zhifei; Tsai, Li-Kai; Munasinghe, Jeeva; Leng, Yan; Fessler, Emily; Chibane, Fairouz L.; Leeds, Peter; Chuang, De‐Maw

doi:10.1161/strokeaha.112.652545

Cited by 96 publications

(80 citation statements)

References 39 publications

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“…In and around the ischemic core, a general decrease of histone H3 acetylation [46][47][48][49][50] as well as of H4 acetylation levels [51][52][53][54] was identified in multiple studies. Vast deacetylation processes occur quickly upon an ischemic insult and induce a fatal course of events.…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetic Mechanisms in Cerebral Ischemia

Schweizer

Meisel

Märschenz

2013

J Cereb Blood Flow Metab

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Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration.

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Section: Dna Methylationmentioning

confidence: 99%

Epigenetic Mechanisms in Cerebral Ischemia

Schweizer

Meisel

Märschenz

2013

J Cereb Blood Flow Metab

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“…In the groups without SD induction, lesion growth in the valproateand vehicle-treated groups was 8±20 mm3 versus 27±52 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl/NaCl application of 161 mm3 (P=0.04 9-11 Intraperitoneal injection of valproate was found to decrease lesion size after ischemic stroke in a rat model, 12 where SDs have been shown to contribute to lesion growth. 13,14 Valproate treatment has also been shown to improve the outcome in a mouse model with SAH induced by subarachnoid blood injection.…”

mentioning

confidence: 89%

“…7,8 Valproate is another effective SD-inhibiting drug. [9][10][11] Intraperitoneal injection of valproate was found to decrease lesion size after ischemic stroke in a rat model, 12 where SDs have been shown to contribute to lesion growth. 13,14 Valproate treatment has also been shown to improve the outcome in a mouse model with SAH induced by subarachnoid blood injection.…”

mentioning

confidence: 97%

Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage

Hamming

Toorn

Rudrapatna

et al. 2017

Stroke

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Delayed cerebral ischemia (DCI) is a common and feared complication after subarachnoid hemorrhage (SAH), which occurs in approximately one third of patients. 1 The mechanisms that are involved in DCI development are largely unknown. Spreading depolarizations (SDs) have been suggested to be associated with DCI in experimental and clinical SAH studies. 2 SDs are waves of depolarizations of neurons and glial cells that spread across brain tissue at a speed of 2 to 6 mm/min. 3 SD is the underlying mechanism of a migraine aura, but may also be associated with other brain diseases. In migraine aura, the tissue recovers from the electrolyte imbalance caused by SDs, presumably through temporary hyperperfusion. 4 However, after an acute ischemic brain insult, such as SAH, SDs may cause permanent tissue injury arising from spreading ischemia because of an inverse hemodynamic response to SD combined with an increased metabolic demand. 2,5 In a small study of SAH patients who needed surgery for their ruptured aneurysm, SDs were recorded by electrocorticography and seemed associated with the development of DCI.5 Inhibition of SD is, therefore, a potential therapeutic approach to prevent brain injury after SAH.Multiple drugs, including antiepileptic drugs and migraine prophylactics, have SD-inhibiting properties. 6 For SAH patients, nimodipine is the only established drug for the clinical prevention of DCI.1 Although the mechanism of action Background and Purpose-Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD-inhibitor valproate reduces brain injury in an SAH rat model with and without experimental SD induction. Methods-Rats were randomized in a 2×2 design and pretreated with valproate (200 mg/kg) or vehicle for 4 weeks. SAH was induced by endovascular puncture of the right internal carotid bifurcation. One day post-SAH, brain tissue damage was measured with T 2 -weighted magnetic resonance imaging, followed by cortical application of 1 mol/L KCl (to induce SDs) or NaCl (no SDs). Magnetic resonance imaging was repeated on day 3 followed by histology to confirm neuronal death. Neurological function was measured with an inclined slope test. Results-In the groups with KCl application, lesion growth between days 1 and 3 was 57±73 mm3 in the valproate-treated versus 237±232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproateand vehicle-treated groups was 8±20 mm3 versus 27±52 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl/NaCl application of 161 mm3 (P=0.04 9-11 Intraperitoneal injection of valproate was found to decrease lesion size after ischemic stroke in a rat model, 12 where SDs have been shown to contribute to lesion growth. 13,14 Valproate treatment has also been shown to improve the outcome in a mouse model with SAH induced by subarachnoid blood injection.15 However, the mechanisms through which valproate may reduce b...

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“…Similar results were obtained by treating rats with VPA during permanent middle cerebral artery occlusion (pMCAO). They exhibit reduced infarct volume, promote functional recovery, enhance angiogenesis by upregulating VEGF [78], and reduce monocytes iniltration [79]. SIRT1 is proangiogenic and increases EC tube formation, especially in post-natal angiogenesis [46].…”

Section: Strokementioning

confidence: 99%

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

Moraga¹,

Lao²,

Zeng³

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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Cardiovascular diseases (CVD) continue to be the leading cause of death in the world despite recent therapeutic advances. Although many CVDs remain incurable, enormous eforts have been placed in harnessing angiogenesis as therapeutics for these diseases. Epigenetics, the modiication of gene expression post-transcriptionally and post-translationally, are important in regulating many biological processes. One of the main post-translational epigenetic modiications, modiication of chromatin structure by the acetylation of histone tails within the chromatin by either histone deacetylases (HDACs) or histone acetyltransferases (HATs), is important in modulating gene transcription and has emerged as an important regulatory player from pathogenesis to therapeutics in CVDs. Particularly, HDACs, which are largely involved in promoting chromatin compaction and hence inhibitions of gene transcription, have been implicated in the pathogenic signalling underlying many aspects of CVDs. Recently, histone modiications have been demonstrated to play important roles in the angiogenesis process. Pharmacological inhibitions of HDACs have displayed promising therapeutic potentials in several pre-clinical models of CVDs where angiogenesis is of paramount importance. There are many evidences proving that pro-and anti-angiogenic therapies-and the impact of epigenetics in these processes-can help to artiicially reconstruct the vasculature in patients with cardiovascular diseases. Conversely, utilising knowledge of HDACs in angiogenesis might help to develop anti-angiogenic therapies in tackling diseases that are characterised with excessive pathological angiogenesis, including cancer and age-related macular degeneration. Understanding the molecular mechanisms underlying HDACs in modulating angiogenesis will undoubtedly beneit future therapeutics development. This chapter focuses on the emerging role of HDACs in angiogenesis and discuss their potentials and challenges in utilising HDAC inhibitors as therapeutics in several major cardiovascular diseases.

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

Cited by 96 publications

References 39 publications

Epigenetic Mechanisms in Cerebral Ischemia

Epigenetic Mechanisms in Cerebral Ischemia

Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

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