Abstract
Purpose: To investigate the effect of asiatic acid on hypoxic ischemia-induced injury in neonatal rats, and the underlying mechanism of action.Methods: Hypoxic-ischemia (HI) neonatal rat model was established via permanent ligation of the carotid artery, followed by hypoxia (exposure to 8 % oxygen and 92 % nitrogen) for 24 h. Immunofluorescence, using fluorescence microscope, was used for the determination of expressions of p-TAK1, NeuN and GFAP. Western blotting was used for assaying protein expression levels, while TUNEL assay was employed for the measurement of apoptosis.Results: Treatment of rats with asiatic acid prior to HI effectively prevented up-regulation of pTAK1 and decreased the count of p-TAK1-containing astrocytes. The proportion of NeuN containing p-TAK1 in HI rat brain cortex was significantly reduced by asiatic acid (p < 0.05). Treatment of rats with asiatic acid suppressed HI- induced up-regulation of pJNK expression. The HI-induced increase in the expression levels of caspase-3, p53 and p-c-Jun in rat brain cortex were reversed by asiatic acid (p < 0.05). The HImediated up-regulation of expressions of p- JNK, caspase-3, p53 and p-c-Jun in rat brain cortex were inhibited significantly by NG25. Asiatic acid treatment also significantly alleviated HI-mediated increase in apoptosis of neurons in rat brain cortex, when compared to model group (p < 0.05).Conclusion: These findings suggest that asiatic acid prevents HI-induced brain injury in neonatal rats via inhibition of neuronal apoptosis. Moreover, it inhibits TAK1 activation, suppresses p-JNK expression and targets pro-apoptotic factors in brain cortex. Therefore, asiatic acid may be a therapeutic agent for the management of HI-induced brain injury.
Highlights
Hypoxia-ischemia (HI) injury has been reported in about 6 out of 1,000 births worldwide, leading to chronic disability and high mortality [1]
Mitogen-activated protein kinase (MAPK), a member of TGF-β-activated kinase-1 (TAK1) family is activated by morphologic proteins of the bones and TGF-β [5]
There was a significant increase in expression of p-TAK1 in rat brain cortex at 24 h after HI, Figure 3: Effect of asiatic acid on GFAP staining in HI
Summary
Hypoxia-ischemia (HI) injury has been reported in about 6 out of 1,000 births worldwide, leading to chronic disability and high mortality [1]. The present study was carried out to investigate the effect of asiatic acid on hypoxia-ischemia-induced injury in neonatal rats, as well as the underlying mechanism. Treatment of the rats with asiatic acid prior to HI induction effectively and dosedependently prevented up-regulation of p-TAK1 in brain cortex, relative to model group. Treatment of rats with asiatic acid at doses of 2 and 4 mg/kg significantly suppressed HI-induced p-TAK1expression in brain cortex. Asiatic acid suppressed p-TAK1-containing GFAP cell count in HI rat brain cortex. The HI model rats had markedly higher proportion of astrocytes containing p-TAK1 in the brain cortex than the sham group (Figure 3). The count of astrocytes containing p-TAK1 in the HI rat brain cortex was significantly decreased on treatment with asiatic acid at a dose of 10 mg/kg
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