Leptin protects brain from ischemia/reperfusion‐induced infarction by stabilizing the blood–brain barrier to block brain infiltration by the blood‐borne neutrophils

Abstract 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.