High-altitude-induced cerebral edema in mice is alleviated by bestatin-mediated blood-brain barrier protection.

Abstract

High-altitude cerebral edema (HACE), arising from exposure to acute hypobaric hypoxia (HH), is a severe and potentially life-threatening evolution of acute mountain sickness (AMS) in high-altitude areas. CD13 is reported to facilitate angiogenesis by degrading extracellular matrix, including tight junctions (TJs). As an effective CD13 inhibitor, bestatin has demonstrated benefits in antiangiogenic therapies for various tumors. However, the impact of bestatin on HACE remains to be elucidated. The present study aims to explore the effects of bestatin in a HACE mouse model. HACE was established by placing 8-wk-old male C57BL/6 mice in a HH environment with a simulated altitude of 7,000 m above sea level for 48 h. Bestatin (1 mg/kg) was administrated intraperitoneally. The effects of bestatin were evaluated with brain water content (BWC) measurements, blood-brain barrier (BBB) integrity detection, and neurological impairment assessments. Increased brain CD13 levels were observed in mice after acute HH exposure. Bestatin significantly lowered BWC and mitigated BBB disruption and naturally improved neurological deficits. Additionally, bestatin curbed HH-induced microglial activation and the loss of astrocytes and neurons. Mechanistically, bestatin suppressed the activation of Hif-1α/NF-κB signaling pathway and reduced Matrix metalloproteinase 9 (MMP-9) expression and activity in the hippocampus of HACE mice. Acute HH-induced upregulation of CD13 primarily damages the BBB by enhancing MMP-9 expression and microglial activation, leading to vasogenic edema, and bestatin, by inhibiting CD13, has the ability to reduce cerebral edema and neurological deficits, showing potential as a future HACE prevention and treatment strategy.NEW & NOTEWORTHY Our findings indicate that acute hypobaric hypoxia exposure can induce a series of changes in cerebral vascular permeability through upregulation of CD13, leading to cerebral edema and neurological deficits. Bestatin, as a specific CD13 inhibitor, can effectively alleviate brain damage caused by acute hypobaric hypoxia exposure and is a potential high-altitude cerebral edema (HACE) therapeutic drug.