Asiatic Acid Attenuates Infarct Volume, Mitochondrial Dysfunction, and Matrix Metalloproteinase-9 Induction After Focal Cerebral Ischemia

Lee, Ki Yong; Bae, Ok Nam; Serfozo, Kelsey; Hejabian, Siamk; Moheb, Ahmad; Reeves, Mathew J.; Rumbeiha, Wilson K.; Fitzgerald, Scott D.; Stein, Gary; Baek, Seung Hoon; Goudreau, John L.; Kassab, Mounzer; Majid, Arshad

doi:10.1161/strokeaha.111.639427

Cited by 51 publications

(39 citation statements)

References 28 publications

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“…It may mediate neuroprotection by protecting mitochondria and inhibiting matrix metalloproteinase-9 induction and activation. 12) The current study has confirmed efficacy in a rat model of embolic focal cerebral ischemia. Most animal stroke models were developed to induce cerebral ischemia within the MCA territory with the intent of mimicking a common clinical scenario.…”

Section: )supporting

confidence: 66%

“…12,14) Each item was graded from 0 (severe deficit) to 3 (no deficit). The grading of all 6 items was added.…”

Section: Animalsmentioning

confidence: 99%

“…9,10) Previously, we reported that AA is neuroprotective in mouse and rat models of focal ischemia. 11,12) We have nowtested AA in an embolic stroke model with t-PA and have evaluated both histological and functional outcomes. We also investigated the influence of AA on mitochondrial injury and subsequent release of cytochrome c (CytoC) and apoptosisinducing factor (AIF).…”

mentioning

confidence: 99%

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Neuroprotective Effect of Asiatic Acid in Rat Model of Focal Embolic Stroke

Lee

Bae

Weinstock

et al. 2014

Biological & Pharmaceutical Bulletin

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Asiatic acid (AA) is a pleiotropic neuroprotective agent that has been shown to attenuate infarct volume in mouse and rat models of focal ischemia and has a long clinically relevant therapeutic time-window. Because in a future trial AA would be administered with tissue-plasminogen activator (t-PA), the only approved acute stroke therapy, we sought to determine the effect of AA when co-administered with t-PA in a rat focal embolic stroke model. Male rats were treated with AA (75 mg/kg) alone, low-dose t-PA (2.5 mg/kg) alone, or a combination of AA and low-dose t-PA at 3 h after inducing embolic stroke. AA significantly reduced infarct volume whereas low-dose t-PA alone did not reduce infarct volume compared with vehicle. Significantly, combination treatment further enhanced reduction of infarct volume versus AA alone. Treatment with AA reduced cytochrome c (CytoC) and apoptosis-inducing factor (AIF) release from brain mitochondria after ischemia. AA was also neuroprotective against L-glutamate-induced toxicity in primary cortical neurons. In summary, combination treatment with AA and low-dose t-PA at 3 h after embolic stroke reduces infarct volume, improves neurological outcome, and provides neuroprotection. The neuroprotective effects of AA were partially associated with reduction of AIF and CytoC release.Key words asiatic acid; tissue-plasminogen activator (t-PA); neuroprotection; rat embolic stroke model; stroke Stroke is a leading cause of mortality and the largest single cause of adult disability worldwide.1) Tissue-plasminogen activator (t-PA) is the only approved pharmacological therapy. However, thrombolysis with t-PA is limited by its narrow time window and the risk of hemorrhagic complications. There is a desperate need for additional safe and effective agents. Asiatic acid (AA) is a triterpene isolated from Centella asiatica which has been widely used as an antioxidant and anti-inflammatory herb in Ayurvedic medicine. AA has also been shown to display neuroprotective properties both in vitro and in vivo.2) In cellular systems, AA is neuroprotective against rotenone and H 2 O 2 -induced injury in SH-SY5Y cells 3) and offers protection against β-amyloid-induced cell death in the neuroblastoma B103 cell line. 4,5) It also reduced H 2 O 2 -related cell death and decreased intracellular free radical concentrations.4) Furthermore, AA derivatives rescue primary rat cortical cells from glutamate-induced toxicity.6) Also, AA was recently reported to alleviate hemodynamic and metabolic alterations via restoring endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) expression, oxidative stress, and inflammation in diet-induced metabolic syndrome rats and to regulates the carbohydrate metabolism by modulating the key regulatory enzymes in diabetic rats. 7,8) AA inhibits adipogenic differentiation of bone marrow stromal cells and attenuates ethanol-induced hepatic injury via suppression of oxidative stress and Kupffer cell activation. 9,10)

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Section: )supporting

confidence: 66%

“…12,14) Each item was graded from 0 (severe deficit) to 3 (no deficit). The grading of all 6 items was added.…”

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

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Neuroprotective Effect of Asiatic Acid in Rat Model of Focal Embolic Stroke

Lee

Bae

Weinstock

et al. 2014

Biological & Pharmaceutical Bulletin

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“…It also has protective effects against neurotoxixity. These effects of AA have been shown in stroke and some degenerative neurodisorders such as Parkinsonism and Alzheimer Disease (7,10,12).…”

Section: Interleukin 1βmentioning

confidence: 98%

“…Some reports stated that AA is a promising agent in the treatment of stroke. AA exerts neuroprotection by maintaining the stability of the blood brain barrier and by protecting the mitochondrial functions (10,12,13,20).…”

mentioning

confidence: 99%

Efficiency of an eastern traditional medicine- asiatic acid on traumatic spinal cord injury: an experimental study

Gurcan

Gürçay²,

Kazanci³

et al. 2015

Turkish Neurosurgery

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The aggressive pathophysiology of SCI contributes to the extension of this devastating condition. A mechanical trauma to the spinal cord triggers an immediate cascade of cellular and biochemical events. Secondary injury processes that take place after the neurological injury cause cell death by glutamate-induced exitotoxicity, inflammation, overproduction of free oxygen radicals, mitochondrial dysfunction, energy failure and apoptosis.

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MicroRNA‐212 promotes the recovery function and vascular regeneration of endothelial progenitor cells in mice with ischemic stroke through inactivation of the notch signaling pathway via downregulating MMP9 expression

Dong

2018

Journal Cellular Physiology

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Ischemic stroke is a refractory disease caused by cerebral ischemic injury, which results in brain dysfunction. This study intends to investigate the effects of microRNA-212 (miR-212) on the recovery function and vascular regeneration of endothelial progenitor cells (EPCs) by inactivation of the Notch signaling pathway by binding to matrix metallopeptidase 9 (MMP9) in mice with ischemic stroke. According to the results of database retrieval systems and data analysis, MMP9 was predicted as a gene related to ischemic stroke and miR-212 is a potential regulating mRNA of MMP9. All 72 healthy adult C57BL6 mice were selected for middle cerebral artery occlusion (MCAO) establishment. Cerebral infarction was observed under triphenyltetrazolium chloride staining. A series of inhibitors, activators, and siRNAs were introduced to the verified regulatory functions for miR-212 governing MMP9 in ischemic stroke. Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and tube-forming ability by tubule formation test. Reverse transcription quantitative polymerase chain reaction and Western blot analysis were used to detect the expressions of miR-212, MMP9, Hes-1, and Notch-1. The corresponding results demonstrated that the area of cerebral infarction and the number of neuronal necrosis increased in the MCAO group in contrast to the sham group. Meanwhile, upregulation of miR-212 or downregulation of MMP9 decreases the expressions of MMP9, Hes-1 Notch-1, increases cell proliferation and tube-forming ability and improves the pathological conditions of EPCs. Our study suggests that miR-212 promotes recovery function and vascular regeneration of EPCs through negative regulation of the Notch signaling pathway via downregulating expression of MMP9, thus provides a clinical theoretical basis for ischemic stroke therapy. K E Y W O R D S endothelial progenitor cells (EPCs), ischemic stroke, metallopeptidase 9 (MMP9), microRNA-212, notch pathway, vascular regeneration J Cell Physiol. 2019;234:7090-7103. wileyonlinelibrary.com/journal/jcp 7090 |

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Asiatic Acid Attenuates Infarct Volume, Mitochondrial Dysfunction, and Matrix Metalloproteinase-9 Induction After Focal Cerebral Ischemia

Cited by 51 publications

References 28 publications

Neuroprotective Effect of Asiatic Acid in Rat Model of Focal Embolic Stroke

Neuroprotective Effect of Asiatic Acid in Rat Model of Focal Embolic Stroke

Efficiency of an eastern traditional medicine- asiatic acid on traumatic spinal cord injury: an experimental study

MicroRNA‐212 promotes the recovery function and vascular regeneration of endothelial progenitor cells in mice with ischemic stroke through inactivation of the notch signaling pathway via downregulating MMP9 expression

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