Abstract
Objective To investigate the influence of melatonin on behavioral and neurological function of rats with focal cerebral ischemia-reperfusion injury via the JNK/FoxO3a/Bim pathway. Methods One hundred and twenty healthy male SD rats were randomized into the model group (Model: the middle cerebral artery occlusion (MCAO) model was constructed and received an equal volume of normal saline containing 5% DMSO), sham operation group (Sham: received no treatment except normal feeding), and low, medium, and high dose of melatonin group (L-MT, M-MT, and H-MT intraperitoneally injected 10, 20, and 40 mg/kg melatonin 30 min after IR, respectively), with 24 rats in each group. Following 24 h of reperfusion, the rats in each of the above groups were tested for neurological deficit symptoms and behavioral changes to screen the rats included in the study. HE and TUNEL stainings were performed to observe pathological changes. Levels of oxidative stress-related indexes, inflammatory factor-related indexes, nuclear factor-κB p65 (NF-κB p65), and interferon-γ (IFN-γ) in the rat brain were measured by ELISA. The JNK/FoxO3a/Bim pathway-related proteins as well as Bcl-2, Caspase-3, and Bax were examined using Western blot. Results Detection of behavioral indicators showed that the MACO model was successfully constructed in rats. L-MT, M-MT, and L-MT groups presented reduced malondialdehyde (MDA), reactive oxygen species (ROS), tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-1β, IFN-γ, NF-κB p65, and apoptosis compared with the Model group (P < 0.05), and the improvement degree was better in the M-MT group versus the L-HT group. Bcl-2 protein expression in the brain tissue of L-MT, M-MT, and H-MT groups increased significantly, while Bax, Caspase-3, p-JNK, p-FoxO3a, and Bim protein expression declined markedly, versus the Model group (P < 0.05). The changes of indexes were greater in the M-MT group compared with that in the L-MT group. No significant difference was observed in all the above indexes between the M-MT group and the H-MT group (P > 0.05). Conclusions In the MACO rat model, melatonin can effectively reduce Bax and Caspase-3 levels by modulating the JNK/FoxO3a/Bim pathway, inhibit neuronal apoptosis, and alleviate neurological deficits by reducing the release of proinflammatory mediators, with anti-inflammatory and antioxidant effects. In addition, 20 mg/kg is the optimal melatonin concentration.
Highlights
Cerebral stroke, known as stroke [1], is a group of acute cerebrovascular diseases caused by sudden rupture of blood vessels in the brain or inability of blood flow to the brain due to vascular blockage, including hemorrhagic stroke (HS) and ischemic stroke (IS) [2, 3]
The behavioral scores of rats were lower in the low dose of melatonin group (L-MT) and M-MT groups compared with the model group (Model) group (P < 0:05), while the behavioral indexes were not significantly different between the high dose of melatonin group (H-MT) group and sham operation group (Sham) group (P > 0:05)
By observing the pathological changes of brain tissue in rats with focal cerebral ischemia, we found that the nerve cells in the Model group were characterized by the loss of cell structure, hyperchromatism, and cytoplasmic laxity, with vacuolar necrosis in some cells, which indicated the presence of irreversible ischemia and hypoxia injury in the brain tissue during reperfusion injury
Summary
Known as stroke [1], is a group of acute cerebrovascular diseases caused by sudden rupture of blood vessels in the brain or inability of blood flow to the brain due to vascular blockage, including hemorrhagic stroke (HS) and ischemic stroke (IS) [2, 3]. The treatment of IS is mainly aimed at reperfusion, neuroprotection, and neurological recovery [5]. In the reperfusion process of recovering blood flow after cerebral ischemia, it will cause more serious damage to brain tissue, namely ischemia-reperfusion injury (IRI) [6]. Because of the long-term ischemia of brain tissue, local inflammation and reactive oxygen species accelerate to produce when the blood supply returns to normal, which, instead of promoting the recovery of brain function, will aggravate brain injury and capillary dysfunction and lead to secondary brain injury, brain edema, hemorrhagic transformation, necrosis, and free radical injury with infarction growth, resulting in strong neuroinflammatory reaction and even death in severe cases [7, 8]. The underlying mechanism and pathway of action of MT after cerebral ischemia remain to be further elucidated
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