Abstract
Ischemic stroke is one of the major causes of disability; widely use of endovascular thrombectomy or intravenous thrombolysis leads to more attention on ischemia-reperfusion injury (I/R injury). Aescin, a natural compound isolated from the seed of the horse chestnut, has been demonstrated anti-inflammatory and antiedematous effects previously. This study was aimed at determining whether aescin could induce protective effects against ischemia-reperfusion injury and exploring the underlying mechanisms in vitro. Primary cultured neurons were subjected to 2 hours of oxygen-glucose deprivation (OGD) followed by 24 hours of simulated reperfusion. Aescin, which worked in a dose-dependent manner, could significantly attenuate neuronal death and reduce lactate dehydrogenase (LDH) release after OGD and simulated reperfusion. Aescin treatment at a concentration of 50 μg/ml provided protection with fewer side effects. Results showed that aescin upregulated the phosphorylation level of PRAS40 and proteins in the mTOR signaling pathway, including S6K and 4E-BP1. However, PRAS40 knockdown or rapamycin treatment was able to undermine and even abolish the protective effects of aescin; meanwhile, the levels of phosphorylation PRAS40 and proteins in the mTOR signaling pathway were obviously decreased. Hence, our study demonstrated that aescin provided neuronal protective effects against I/R injury through the PRAS40/mTOR signaling pathway in vitro. These results might contribute to the potential clinical application of aescin and provide a therapeutic target on subsequent cerebral I/R injury.
Highlights
Stroke is a major cause of disability globally; 85% are ischemic and responsible for approximately 5 million deaths every year [1, 2]
To determine whether aescin treatment can provide protective effects against I/R injury, we applied the oxygen-glucose deprivation (OGD) and reperfusion model to simulate the situation of neuronal I/R injury in vitro
Consistent with our previous study [17], rapamycin significantly inhibited the phosphorylation of the mammalian target of rapamycin (mTOR) signaling pathway, impaired the protective effects of aescin treatment, and end up with severer neuronal I/R injury. All of these evidences strongly suggest that aescin treatment protects primary cultured neurons against I/R injury and the proline-rich Akt substrate of 40 kDa (PRAS40)/mTOR signaling pathway is necessary for the protective effects of aescin
Summary
Stroke is a major cause of disability globally; 85% are ischemic and responsible for approximately 5 million deaths every year [1, 2]. The commonest cause of ischemic stroke is pathophysiological thrombosis or thromboembolism giving rise to cerebral arterial occlusion [3]. Endovascular thrombectomy and intravenous thrombolysis have been widely recommended and performed to treat patients with acute ischemic stroke. Not all patients end up with good outcomes after endovascular thrombectomy or intravenous thrombolysis. Owing to that I/R injury is a series of complex pathophysiological mechanisms and involves various signaling pathways [5,6,7,8], till no effective measures have been developed for cerebral I/R injury in a clinic
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