A single dose of melatonin fails to reduce brain damage following cardiac I/R injury

Abstract

AbstractBackgroundCardiac ischemia/reperfusion (I/R) injury caused the detrimental effects not only to the heart but also to the brain. We previously reported that cardiac I/R injury led to blood brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and microglial hyperactivation, resulting in amyloid beta (Aβ) aggregation. Pretreatment with melatonin showed a neuroprotective effect against cerebral I/R injury. However, the effects of melatonin on the brain pathologies following cardiac I/R injury have never been investigated. Therefore, we hypothesize that melatonin treatment at various time points of cardiac I/R including pretreatment, during cardiac ischemia, and at the onset of reperfusion attenuate brain damages via decreasing inflammation, mitochondrial dysfunction, and Alzheimer’s proteins levels in rats with cardiac I/R injury.MethodMale Wistar rats (n=45) were subjected to either sham operation (n=5) or cardiac I/R injury (30 min of cardiac ischemia, followed by 120 min of reperfusion). Rats were divided into 4 groups (n=10/group) including 1) vehicle (normal saline solution), 2) Pretreatment with melatonin, 3) Melatonin treatment during cardiac ischemia (15 min after ischemia), and 4) Melatonin treatment at the onset of reperfusion. Melatonin was administered at the dose of 10 mg/kg via intravenous injection. At the end of reperfusion, brains were rapidly removed, and brain tissue was used to determine brain mitochondrial function, microglial morphology, BBB and Alzheimer’s protein expression.ResultCardiac I/R led to brain inflammation as indicated by increasing the number of activated microglia and reducing number of resident microglia. Moreover, brain mitochondrial dysfunction was observed after cardiac I/R as indicated by increasing mitochondrial oxidative stress, mitochondrial membrane depolarization and mitochondrial swelling. Our results also showed that Aβ/APP and p‐Tau/Tau were increased after cardiac I/R, together with a reduction of occludin protein levels. These data suggested that cardiac I/R led to brain damages. Treatment with melatonin at all time points did not affect the number of activated and resident microglia, brain mitochondrial function, Alzheimer’s related proteins, or BBB protein after cardiac I/R, when compared with vehicle group (Figure 1). ConclusionA single dose of melatonin administration failed to reduce brain damage following cardiac I/R injury.