Valproic Acid Attenuates Blood–Brain Barrier Disruption in a Rat Model of Transient Focal Cerebral Ischemia: The Roles of HDAC and MMP-9 Inhibition

Wang, Zhifei; Leng, Yan; Tsai, Li-Kai; Leeds, Peter; Chuang, De‐Maw

doi:10.1038/jcbfm.2010.195

Cited by 208 publications

(188 citation statements)

References 15 publications

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“…These results indicated that the mechanism underlying BBB protection may be associated with the inhibition of AQP-4 and MMP-9 function. Studies have additionally demonstrated that propofol inhibited the expression of AQP-4 in astroglia in vitro (23) and decreased the expression of MMP-9 in vivo (24). In the present study, the expression levels of AQP-4 and MMP-9 were markedly lower in groups P1 and P2 than those in group S, indicating that treatment with propofol inhibited the expression of these proteins.…”

Section: Discussionmentioning

confidence: 45%

“…Inhibitors of AQP-4 and MMP-9 may protect the BBB to a certain extent (20). The extent of brain edema observed in cerebral ischemia/reperfusion animals was significantly reduced following inhibition, and the animals demonstrated an improved prognosis (21)(22)(23). These results indicated that the mechanism underlying BBB protection may be associated with the inhibition of AQP-4 and MMP-9 function.…”

Section: Discussionmentioning

confidence: 56%

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Propofol post-conditioning protects the blood brain barrier by decreasing matrix metalloproteinase-9 and aquaporin-4 expression and improves the neurobehavioral outcome in a rat model of focal cerebral ischemia-reperfusion injury

Liang

Miao

et al. 2015

Molecular Medicine Reports

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Abstract. Propofol, an intravenous anesthetic, inhibits neuronal apoptosis induced by ischemic stroke, protects the brain from ischemia/reperfusion injury and improves neuronal function. However, whether propofol is able to protect the blood brain barrier (BBB) and the underlying mechanisms have remained to be elucidated. In the present study, a rat model of cerebral ischemia/reperfusion was established, using a thread embolism to achieve middle cerebral artery occlusion. Rats were treated with propofol (propofol post-conditioning) or physiological saline (control) administered by intravenous injection 30 min following reperfusion. Twenty-four hours following reperfusion, neurobehavioral manifestations were assessed. The levels of cephaloedema, damage to the BBB and expression levels of matrix metalloproteinase-9 (MMP-9), aquaporin-4 (AQP-4) and phosphorylated c-Jun N-terminal kinase (pJNK) were determined in order to evaluate the effects of propofol on the BBB. In comparison to the cerebral ischemia/reperfusion group, the levels of brain water content and Evans blue content, as well as the expression levels of MMP-9, AQP-4 and pJNK were significantly reduced in the propofol post-conditioning group. These results indicated that propofol post-conditioning improved the neurobehavioral manifestations and attenuated the BBB damage and cephaloedema induced following cerebral ischemia/reperfusion. This effect may be due to the inhibition of MMP-9 and AQP-4 expression, and the concurrent decrease in JNK phosphorylation.

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Section: Discussionmentioning

confidence: 45%

Section: Discussionmentioning

confidence: 56%

Propofol post-conditioning protects the blood brain barrier by decreasing matrix metalloproteinase-9 and aquaporin-4 expression and improves the neurobehavioral outcome in a rat model of focal cerebral ischemia-reperfusion injury

Liang

Miao

et al. 2015

Molecular Medicine Reports

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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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“…The DX+RT group received 100 mg/kg intramuscular (IM) DX monohydrate solution (200 mg per mL ready solution for injection) (Doksilin LA, Provet; İstanbul, Turkey). The VA dose required for MMP inhibition was determined on the basis of that reported in a previous study (14). DX was administered as a single dose of 100 mg/kg since the recommended DX longacting injectable dose was 70-100 mg/kg in rat medication (15).…”

Section: Methodsmentioning

confidence: 99%

Anti-inflammatory and Anti-apoptotic Effect of Valproic Acid and Doxycycline Independent from MMP Inhibition in Early Radiation Damage

Hoşgörler

Keleş

Tanriverdi-Akhisaroglu

et al. 2016

Balkan Med J

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Background: Matrix metalloproteinase (MMP) inhibitors decrease inflammation in normal tissues and suppress cancer progress in normal tissues. Valproic acid (VA) and doxycycline (DX) are MMP inhibitors that have radio-protective effects. Their ability to inhibit MMPs in irradiated tissue is unknown and the role of MMPs in radio-protective effects has not been tested to date. Aims: The purpose of this study was to examine whether administration of VA and DX to rats before irradiation affects tissue inflammation and apoptosis in the early phase of radiation, and whether the effect of these drugs is mediated by MMP inhibition. Study Design: Animal experimentation. Methods: Twenty-six Wistar rats were randomized into four groups: control (CTRL), radiation (RT), VA plus radiation (VA+RT), and DX plus radiation (DX+RT). Three study groups were exposed to a single dose of abdominal 10 Gy gamma radiation; the CTRL group received no radiation. Single doses of VA 300 mg/kg and DX 100 mg/kg were administered to each rat before radiation and all rats were sacrificed 8 hours after irradiation, at which point small intestine tissue samples were taken for analyses. Levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and matrix metalloproteinases (MMP-2 and MMP 9) were measured by ELISA, MMP activities were measured by gelatin and casein zymography and apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results: VA decreased the levels of TNF-α and IL-1β proteins insignificantly and decreased apoptosis significantly in the irradiated tissue, but did not inhibit MMPs. In contrast, VA protected the basal MMP activities, which decreased in response to irradiation. No effect of DX was observed on the levels of inflammatory cytokines or activities of MMPs in the early phases of radiation apoptosis. Conclusion: Our findings indicated that VA protects against inflammation and apoptosis, and DX exhibits anti-apoptotic effects in early radiation and these effects are independent from MMP inhibition.

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Valproic Acid Attenuates Blood–Brain Barrier Disruption in a Rat Model of Transient Focal Cerebral Ischemia: The Roles of HDAC and MMP-9 Inhibition

Cited by 208 publications

References 15 publications

Propofol post-conditioning protects the blood brain barrier by decreasing matrix metalloproteinase-9 and aquaporin-4 expression and improves the neurobehavioral outcome in a rat model of focal cerebral ischemia-reperfusion injury

Propofol post-conditioning protects the blood brain barrier by decreasing matrix metalloproteinase-9 and aquaporin-4 expression and improves the neurobehavioral outcome in a rat model of focal cerebral ischemia-reperfusion injury

Epigenetic Mechanisms in Cerebral Ischemia

Anti-inflammatory and Anti-apoptotic Effect of Valproic Acid and Doxycycline Independent from MMP Inhibition in Early Radiation Damage

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