Protective Effect of Low-Dose Alcohol Consumption against Post-Ischemic Neuronal Apoptosis: Role of L-PGDS.
Protective Effect of Low-Dose Alcohol Consumption against Post-Ischemic Neuronal Apoptosis: Role of L-PGDS.
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DOI：
10.3390/ijms23010133
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发表时间：
2021-12-23
影响因子：
5.6
通讯作者：
Sun H
中科院分区：
文献类型：
--
作者：
Li C;Li J;Loreno EG;Miriyala S;Panchatcharam M;Sun H
缺血性中风是全世界成年人永久性残疾和死亡的主要原因之一。细胞凋亡是导致缺血后神经元死亡的主要因素。我们之前发现，低剂量饮酒（LAC）可以防止短暂性局灶性脑缺血后梗塞周围皮层的神经元凋亡。脂质运载蛋白型前列腺素 D2 合酶 (L-PGDS) 主要位于中枢神经系统 (CNS) 中，先前已被证明可以抑制神经元凋亡。因此，我们确定L-PGDS是否参与LAC对缺血后神经元凋亡的保护作用。 C57BL/6J 背景下的野生型 (WT)、CaMKIIαCreERT2/+/L-PGDS+/+ 和 CaMKIIαCreERT2/+/L-PGDSflox/flox 小鼠每天用乙醇或体积匹配的水灌胃一次，持续 8 周。在第四周，CaMKIIαCreERT2/+/L-PGDS+/+ 和 CaMKIIαCreERT2/+/L-PGDSflox/flox 小鼠腹腔内给予他莫昔芬（2 mg/天）5天。 AT-56（30 mg/kg/天）是一种 L-PGDS 的选择性抑制剂，从第五周开始给 AT-56 治疗的 WT 小鼠口服给药，持续 4 周。在 90 分钟单侧大脑中动脉闭塞 (MCAO) 后再灌注 24 小时，测量脑缺血/再灌注 (I/R) 损伤、TUNEL 阳性神经元和裂解的 caspase-3 阳性神经元。我们发现 0.7 g/kg/天但不是 2.8 g/kg/天的乙醇显着上调大脑皮层中的 L-PGDS。此外，0.7 g/kg/天的乙醇可减轻 WT 和 CaMKIIαCreERT2/+/L-PGDS+/+ 小鼠的脑缺血/再灌注 (I/R) 损伤以及梗塞周围皮质中 TUNEL 阳性和裂解的 caspase-3 阳性神经元。此外，在 AT-56 处理的 WT 和 CaMKIIαCreERT2/+/L-PGDSflox/flox 小鼠中，0.7 g/kg/天乙醇的神经保护作用有所减轻。我们的研究结果表明，LAC 可能通过上调的 L-PGDS 抑制缺血后神经元凋亡，从而预防脑缺血再灌注损伤。
Ischemic stroke is one of the leading causes of permanent disability and death in adults worldwide. Apoptosis is a major element contributing to post-ischemic neuronal death. We previously found that low-dose alcohol consumption (LAC) protects against neuronal apoptosis in the peri-infarct cortex following transient focal cerebral ischemia. Lipocalin-type prostaglandin D2 synthase (L-PGDS), which is mainly localized in the central nervous system (CNS), was previously shown to inhibit neuronal apoptosis. Therefore, we determined whether L-PGDS is involved in the protective effect of LAC against post-ischemic neuronal apoptosis. Wild-type (WT), CaMKIIαCreERT2/+/L-PGDS+/+, and CaMKIIαCreERT2/+/L-PGDSflox/flox mice on a C57BL/6J background were gavage fed with ethanol or volume-matched water once a day for 8 weeks. Tamoxifen (2 mg/day) was given intraperitoneally to CaMKIIαCreERT2/+/L-PGDS+/+ and CaMKIIαCreERT2/+/L-PGDSflox/flox mice for 5 days during the fourth week. AT-56 (30 mg/kg/day), a selective inhibitor of L-PGDS, was given orally to AT-56-treated WT mice from the fifth week for four weeks. Cerebral ischemia/reperfusion (I/R) injury, TUNEL-positive neurons, and cleaved caspase-3-positive neurons were measured at 24 h of reperfusion after a 90 min unilateral middle cerebral artery occlusion (MCAO). We found that 0.7 g/kg/day but not 2.8 g/kg/day ethanol significantly upregulated L-PGDS in the cerebral cortex. In addition, 0.7 g/kg/day ethanol diminished cerebral ischemia/reperfusion (I/R) injury and TUNEL-positive and cleaved caspase-3-positive neurons in the peri-infarct cortex in WT and CaMKIIαCreERT2/+/L-PGDS+/+ mice. Furthermore, the neuroprotective effect of 0.7 g/kg/day ethanol was alleviated in AT-56-treated WT and CaMKIIαCreERT2/+/L-PGDSflox/flox mice. Our findings suggest that LAC may protect against cerebral I/R injury by suppressing post-ischemic neuronal apoptosis via an upregulated L-PGDS.