Abstract
Leonurine, also named SCM-198, which was extracted from Herba leonuri, displayed a protective effect on various cardiovascular and brain diseases, like ischemic stroke. Ischemic stroke which is the leading cause of morbidity and mortality, ultimately caused irreversible neuron damage. This study is aimed at exploring the possible therapeutic potential of SCM-198 in the protection against postischemic neuronal injury and possible underlying mechanisms. A transient middle cerebral artery occlusion (tMCAO) rat model was utilized to measure the protective effect of SCM-198 on neurons. TEM was used to determine neuron ultrastructural changes. The brain slices were stained with Nissl staining solution for Nissl bodies. Fluoro-Jade B (FJB) was used for staining the degenerating neurons. In the oxygen-glucose deprivation and re-oxygenation (OGD/R) model of bEnd.3 cells treated with SCM-198 (0.1, 1, 10 μM). Then, the bEnd.3 cells were cocultured with SH-SY5Y cells. Cell viability, MDA level, CAT activity, and apoptosis were examined to evaluate the cytotoxicity of these treatments. Western blot and immunofluorescent assays were used to examine the expression of protein related to the p-STAT3/NOX4/Bcl-2 signaling pathway. Coimmunoprecipitation was performed to determine the interaction between p-STAT3 and NOX4. In the transient middle cerebral artery occlusion (tMCAO) rat model, we found that treatment with SCM-198 could ameliorate neuron morphology and reduce the degenerating cell and neuron loss. In the in vitro model of bEnd.3 cell oxygen-glucose deprivation and reoxygenation (OGD/R), treatment with SCM-198 restored the activity of catalase (CAT), improved the expression of Cu-Zn superoxide dismutase (SOD1), and decreased the malondialdehyde (MDA) production. SCM-198 treatment prevented OGD/R-induced cell apoptosis as indicated by increased cell viability and decreased the number of TUNEL-positive cells, accompanied with upregulation of Bcl-2 and Bcl-xl protein and downregulation Bax protein. The results were consistent with SH-SY5Y cells which coculture with bEnd.3 cells. The forthcoming study revealed that SCM-198 activated the p-STAT3/NOX4/Bcl-2 signaling pathway. All the data indicated that SCM-198 protected against oxidative stress and neuronal damage in in vivo and in vitro injury models via the p-STAT3/NOX4/Bcl-2 signaling pathway. Our results suggested that SCM-198 could be the potential drug for neuroprotective effect through stabilizing endothelial cell function.
Highlights
Stroke is one of the leading cause of morbidity and mortality worldwide [1], owing to its incredibly short therapeutic time window and fewer effective emergency medicines, tissue-type plasminogen activator serving as priority therapeutic drug in ischemic stroke, with only 10% patients of which applicable to this therapy [2]
The results indicated that SCM-198, 1 and 10 μM, protected against apoptosis through improving the level of p-signal transducers and transcription 3 (STAT3) and inhibiting the expression of NOX4, modulated p-Akt, the proteins which were involved in cell apoptosis (Figures 5(g)–5(i))
We demonstrated that NOX4 and apoptosis pathway mediated the protective effects of SCM198 on endothelial cells and neurons during stroke in vivo and in vitro
Summary
Stroke is one of the leading cause of morbidity and mortality worldwide [1], owing to its incredibly short therapeutic time window and fewer effective emergency medicines, tissue-type plasminogen activator (tPA) serving as priority therapeutic drug in ischemic stroke, with only 10% patients of which applicable to this therapy [2]. In the ischemic stroke, secondary damage led by reperfusion will worsen prognosis including a breakdown of blood-brain barrier (BBB), inflammation, oxidative stress, excitotoxicity, and irreversible neuronal damage [4]. Recent researches demonstrated that NOX4 exerted the protective effect against blood-brain barrier breakdown, oxidative stress, and neuronal apoptosis during ischemic stroke [12, 13]
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