The cellular and molecular mechanisms underlying leptin‐mediated brain protection against cerebral ischemia were investigated at the blood–brain barrier (BBB) and neutrophil level. Through the ischemia/reperfusion (I/R) animal model, we found that leptin expression level was significantly decreased in ischemic hemisphere. Brain injection with leptin (15 μg/kg, intracisternally) could block the I/R‐increased BBB permeability, activation of matrix metallopeptidase 9 (MMP‐9) and brain infiltration of blood–borne neutrophils to reduce the infarct volume of ischemic brain. The brain expression level of tight junction protein ZO‐1 as well as number and motility of neutrophils in blood was all increased by the same injection, indicating BBB stability (rather than reduction in neutrophils) played a major role in the leptin‐inhibited brain infiltration of neutrophils. Leptin‐mediated protection of BBB was further confirmed in vitro, through a BBB cellular model under the in vitro ischemic condition (G/R: glucose–oxygen–serum deprivation followed by GOS restoration). The results showed that leptin again could block the G/R‐increased neutrophil adherence to EC layer as well as BBB permeability, likely by stimulating the endothelial expression of ZO‐1 and VE‐Cadherin. The study has demonstrated that leptin could protect ischemic brain via multiple ways (other than neuronal protection), by inhibiting the BBB permeability, brain infiltration of the blood‐borne neutrophils and neutrophil adherence to vascular ECs. The role of leptin in vascular biology of stroke could further support its therapeutic potential in other neurodegenerative diseases, associated with BBB disorder.

中文翻译：

---

瘦素通过稳定血脑屏障来阻止脑血中性粒细胞浸润，从而保护大脑免受缺血/再灌注引起的梗塞

在血脑屏障（BBB）和中性粒细胞水平上研究了瘦素介导的脑保护作用以抵抗脑缺血的细胞和分子机制。通过缺血/再灌注（I / R）动物模型，我们发现在缺血半球中，瘦素的表达水平显着降低。脑内注射瘦素（15μg/ kg，脑池内）可阻止I / R增加的BBB通透性，基质金属肽酶9（MMP-9）的激活以及血源性中性粒细胞的脑浸润，以减少缺血性脑的梗塞体积。相同的注射量会增加紧密连接蛋白ZO-1的大脑表达水平以及血液中嗜中性粒细胞的数量和运动，表明BBB的稳定性（而不是中性粒细胞减少）在瘦素抑制的中性粒细胞脑浸润中起主要作用。瘦素介导的BBB保护在体外缺血条件下通过BBB细胞模型得到进一步证实（G / R：葡萄糖-氧气-血清剥夺，然后进行GOS还原）。结果表明，瘦素可再次刺激ZO-1和VE-钙黏着蛋白的内皮表达，从而阻止G / R增加的中性粒细胞对EC层的粘附以及BBB的通透性。这项研究表明，瘦素可以通过抑制血脑屏障通透性，血源性中性粒细胞的脑浸润和中性粒细胞对血管内皮细胞的粘附，通过多种方式（除了神经元保护作用）保护缺血性脑。