高血糖加重缺血性脑损伤 ERK1/2 激活细胞自噬和线粒体分裂。
Hyperglycemia aggravates ischemic brain damage ERK1/2 activated cell autophagy and mitochondrial fission.
机构信息
Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan, China.
Neuroscience Center, General Hospital of Ningxia Medical University, Yinchuan, China.
出版信息
Front Endocrinol (Lausanne). 2022 Aug 5;13:928591. doi: 10.3389/fendo.2022.928591. eCollection 2022.
BACKGROUND
Hyperglycemia is one of the major risk factors for stroke and stroke recurrence, leading to aggravated neuronal damage after cerebral ischemia/reperfusion (I/R). ERK1/2 signaling pathway plays a vital role in cerebral ischemic injury. However, the role of the ERK1/2 pathway in hyperglycemia-aggravated ischemic brain damage is not clear.
METHODS
Streptozotocin (STZ; 50 mg/kg)-induced diabetes (blood glucose ≥12 mmol/L) or control groups in adult Sprague-Dawley rats were further subdivided into I/R (carotid artery/vein clamping), I/R + PD98059 (I/R plus ERK1/2 inhibitor), and Sham-operated groups (n = 10 each). Neurobehavioral status (Neurological behavior scores) and the volume of the cerebral infarction (TTC staining); brain mitochondrial potential (JCI ratio test) and cell apoptosis (TUNEL assay); RAS protein expression, phosphorylated/total ERK1/2 and Drp-1 (Dynamic-related protein 1) protein levels (Western blotting); mitochondrial fusion-related proteins mitofusin-1/2 (Mfn1/2), optic atrophy (OPA-1) and mitochondrial fission 1 (Fis1), and autophagy-associated proteins Beclin-1, LC3-I/II and P62 (Western blotting and immunohistochemistry) were analyzed.
RESULTS
The I/R + PD98059 group demonstrated better neurobehavior on the 1 (p < 0.05) and the 3 day (p < 0.01) than the I/R group. Compared to the Sham group, cerebral ischemia/reperfusion brought about neuronal damage in the I/R group (p <0.01). However, treatment with PD98059 showed an improved situation with faster recovery of mitochondrial potential and less apoptosis of neuronal cells in the I/R + PD98059 group (p < 0.01). The I/R group had a higher-level expression of RAS and phosphorylated ERK1/2 and Drp-1 than the diabetes mellitus (DM) group (p < 0.01). The PD98059 treated group showed decreased expression of p-ERK1/2, p-Drp-1, Fis1, and Beclin-1, LC3-I/II and P62, but increased Mfn1/2 and OPA-1 than the I/R group (p < 0.01).
CONCLUSION
Hyperglycemia worsens cerebral ischemia/reperfusion-induced neuronal damage ERK1/2 activated cell autophagy and mitochondrial fission.
背景
高血糖是中风和中风复发的主要危险因素之一，导致脑缺血/再灌注（I/R）后神经元损伤加重。ERK1/2 信号通路在脑缺血损伤中起着至关重要的作用。然而，ERK1/2 通路在高血糖加重缺血性脑损伤中的作用尚不清楚。
方法
链脲佐菌素（STZ；50mg/kg）诱导的糖尿病（血糖≥12mmol/L）或对照组成年 Sprague-Dawley 大鼠进一步分为 I/R（颈总动脉/颈静脉夹闭）、I/R+PD98059（I/R 加 ERK1/2 抑制剂）和假手术组（每组 10 只）。神经行为状态（神经行为评分）和脑梗死体积（TTC 染色）；脑线粒体电位（JCI 比值试验）和细胞凋亡（TUNEL 检测）；RAS 蛋白表达、磷酸化/总 ERK1/2 和 Drp-1（动态相关蛋白 1）蛋白水平（Western 印迹）；线粒体融合相关蛋白线粒体融合蛋白 1/2（Mfn1/2）、视神经萎缩（OPA-1）和线粒体分裂 1（Fis1）和自噬相关蛋白 Beclin-1、LC3-I/II 和 P62（Western 印迹和免疫组化）进行分析。
结果
与 I/R 组相比，I/R+PD98059 组在第 1 天（p<0.05）和第 3 天（p<0.01）的神经行为更好。与假手术组相比，脑缺血再灌注导致 I/R 组神经元损伤（p<0.01）。然而，PD98059 治疗组显示出更好的情况，即 I/R+PD98059 组的线粒体电位恢复更快，神经元细胞凋亡减少（p<0.01）。与糖尿病组相比，I/R 组 RAS 和磷酸化 ERK1/2、Drp-1 的表达水平更高（p<0.01）。PD98059 处理组的 p-ERK1/2、p-Drp-1、Fis1、Beclin-1、LC3-I/II 和 P62 的表达水平降低，但 Mfn1/2 和 OPA-1 的表达水平升高（p<0.01）。
结论
高血糖加重脑缺血/再灌注诱导的神经元损伤，激活 ERK1/2 细胞自噬和线粒体分裂。
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