Myeloid differentiation factor 2 inhibitor, 2i‐10, alleviates dendritic spine loss in rats with cardiac ischemia‐reperfusion injury via decreasing brain inflammation

Abstract

Previous studies have been reported that cardiac ischemia/reperfusion (I/R) injury, which is a life-threatening cardiovascular event, caused brain damage by provoked brain inflammation. 2i-10, a cinnamamide derivative, is able to inhibit inflammatory cytokines production through a direct inhibition of myeloid differentiation factor 2 (MD2). However, the effects of 2i-10 on brain pathologies during cardiac I/R injury have not been investigated. We hypothesized that treatment with 2i-10 at the onset of reperfusion ameliorates brain damage via reducing brain mitochondrial dysfunction, dendritic spine loss, beta-amyloid (Aβ) aggregations and inflammatory cytokine levels in the setting of cardiac I/R injury. Male rats were subjected to either sham (n=6) or cardiac I/R operation (n=36). Cardiac I/R was induced by a ligation of left anterior descending artery for 30 min to induce ischemia, followed by 120 min of reperfusion. Rats in cardiac I/R group were divided into 3 groups (n=12/group); vehicle, 2i-10 at 20 mg/kg, and 2i-10 at 40 mg/kg. 2i-10 was injected via femoral vein at the onset of reperfusion. At the end of protocol, brains were removed to investigate mitochondrial function (mitochondrial ROS, mitochondrial swelling, mitochondrial depolarization), dendritic spine density, Aβ and inflammatory cytokine (TNF-α) protein expression. Our results demonstrated that brain inflammation was increased after cardiac I/R injury as indicated by increasing TNF-α protein expression. Moreover, brain mitochondrial dysfunction was found as showed by increasing mitochondrial ROS level, mitochondrial depolarization, mitochondrial swelling, which associated with Aβ aggregation and dendritic spine loss. Treatment with 2i-10 at the onset of reperfusion effectively reduced TNF-α protein expression, mitochondrial ROS levels and mitochondrial swelling. Furthermore, 2i-10 reduced the loss of dendritic spine, but it did not alter Aβ levels and mitochondrial membrane potential after cardiac I/R injury (Figure 1). Data from our study also showed that 20 and 40 mg/kg of 2i-10 provided similar benefits to the brain in rats with cardiac I/R injury. Treatment with MD-2 inhibitor at the onset of reperfusion reduced brain inflammation and mitochondrial dysfunction, leading to the reduction of dendritic spine loss in rats with cardiac I/R injury.