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

Abstract

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)

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

“…Numerous active CAW compounds are currently being examined in our laboratory to elucidate their effects on cognitive function, oxidative stress, and mitochondrial biogenesis and function. Previously, in vitro studies have shown that both CAW whole extract and isolated compounds (detailed in a review [32]) facilitate neurite outgrowth [6,28,106], and elicit neuroprotection [107][108][109][110][111]. The neurological effects of certain CAW active compounds are also observed in vivo, increasing learning and memory while providing neuroprotection in rodents [2,13,112].…”

Asiatic Acid Interferes with Invasion and Proliferation of Breast Cancer Cells by Inhibiting WAVE3 Activation through PI3K/AKT Signaling Pathway

“…Specifically, asiatic acid has outstanding advantages in reducing inflammation, caring for the skin, and protecting the liver and nerves. It protects the skin from light damage [26,27], prevents liver fibrosis [28,29], protects neurons [30,31],and so forth, and hence it is better at preventing and fighting against skin cancer, liver cancer, glioma, and glioblastoma. Currently, asiatic acid has not been used clinically in the treatment of patients with a tumor.…”

Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise

“…Due to its abundant presence in many plants, AA used as a main biomarker component in numerous plant extract based formulations for standardization and quality assurance (Lee et al, 2014 ). The contents of AA in numerous plant species cultivated, harvested, and habituated from diverse geographic and biodiversity regions have been studied using modern bioanalytical instrumentation techniques.…”