Abstract
Cryptotanshinone (CTs), an active component isolated from the root of Salvia miltiorrhiza (SM), has been shown to exert potent neuroprotective property. We here established an oxygen-glucose deprivation/recovery (OGD/R)-injured Neurovascular Unit (NVU) model in vitro to observe the neuroprotective effects of CTs on cerebral ischemia/reperfusion injury (CIRI), and explore the underlying mechanisms. CTs was observed to significantly inhibit the OGD/R-induced neuronal apoptosis, and decease the activation of Caspase-3 and the degradation of poly-ADP-ribose polymerase (PARP), as well as the increase of Bax/Bcl-2 ratio in neurons under OGD/R condition. The inhibitory effects of CTs on neuron apoptosis were associated with the blocking of mitogen-activated protein kinase (MAPK) signaling pathway. CTs also remarkably ameliorated OGD/R-induced reduction of transepithelial electrical resistance (TEER) values and the increase of transendothelial permeability coefficient (Pe) of sodium fluorescein (SF) by upregulating the expression of ZO-1, Claudin-5, and Occludin in brain microvascular endothelial cells (BMECs), which might be related to the down-regulation of matrix metalloproteinase (MMP)-9 expression. Based on these findings, CTs may play a neuroprotective role in OGD/R injure in NVU models in vitro by inhibiting cell apoptosis and alleviating the damage of blood-brain barrier (BBB).
Highlights
Stroke is the second leading cause of morbidity and mortality worldwide, with acute ischemic stroke (AIS) making up more than 80% of all the cases [1]
Our results demonstrated that the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun amino terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) was significantly increased in the neurons of Neurovascular Unit (NVU) model in vitro exposed to oxygen-glucose deprivation/recovery (OGD/R)
Our results indicated that the protective effects of CTs against neuronal apoptosis induced by OGD/R could associate with suppressing the activation of MAPK signalings
Summary
Stroke is the second leading cause of morbidity and mortality worldwide, with acute ischemic stroke (AIS) making up more than 80% of all the cases [1]. Rapid restoration of blood supply is a critical therapeutic strategy for AIS, but it can bring secondary damage and Effects of CTs on CIRI further lead to more serious disturbance in the function of nervous system, called cerebral ischemia/reperfusion injury (CIRI). NVU is regarded as the basic structural and functional unit of brain, and mainly including neurons, astrocytes, microglia, microvascular endothelial cells, pericytes, even with basement membrane, and extracellular matrix. This concept shows the interactions among these types of cells, and reflects their roles in the origination and development of brain diseases [5]. NVU has become an important model for studying multi-target and multi-level therapy for brain diseases
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