Abstract
The purpose of the present experiment was to investigate whether hexahydrocurcumin (HHC) attenuates brain damage and improves functional outcome via the activation of antioxidative activities, anti-inflammation, and anti-apoptosis following cerebral ischemia/reperfusion (I/R). In this study, rats with cerebral I/R injury were induced by a transient middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion. The male Wistar rats were randomly divided into five groups, including the sham-operated, vehicle-treated, 10 mg/kg HHC-treated, 20 mg/kg HHC-treated, and 40 mg/kg HHC-treated I/R groups. The animals were immediately injected with HHC by an intraperitoneal administration at the onset of cerebral reperfusion. After 24 h of reperfusion, the rats were tested for neurological deficits, and the pathology of the brain was studied by 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, and terminal deoxynucleotidyltransferase UTP nick end labeling (TUNEL) staining. In addition, the brain tissues were prepared for protein extraction for Western blot analysis, a malondialdehyde (MDA) assay, a nitric oxide (NO) assay, a superoxide dismutase (SOD) assay, a glutathione (GSH) assay, and a glutathione peroxidase (GSH-Px) assay. The data revealed that the neurological deficit scores and the infarct volume were significantly reduced in the HHC-treated rats at all doses compared to the vehicle group. Treatment with HHC significantly attenuated oxidative stress and inflammation, with a decreased level of MDA and NO and a decreased expression of NF-κB (p65) and cyclooxygenase-2 (COX-2) in the I/R rats. HHC also evidently increased Nrf2 (nucleus) protein expression, heme oxygenase-1 (HO-1) protein expression, the antioxidative enzymes, and the superoxide dismutase (SOD) activity. Moreover, the HHC treatment also significantly decreased apoptosis, with a decrease in Bax and cleaved caspase-3 and an increase in Bcl-XL, which was in accordance with a decrease in the apoptotic neuronal cells. Therefore, the HHC treatment protects the brain from cerebral I/R injury by diminishing oxidative stress, inflammation, and apoptosis. The antioxidant properties of HHC may play an important role in improving functional outcomes and may offer significant neuroprotection against I/R damage.
Highlights
Stroke is one of the leading causes of mortality worldwide and is a major cause of long-term disability in people in both developed and developing countries [1, 2]
Reperfusion is critical in the treatment of ischemic stroke
The cerebral blood flow (CBF) returned to a level higher than 70% of the baseline after reperfusion in all the I/R groups without any significant differences detected among the groups (P > 0.05)
Summary
Stroke is one of the leading causes of mortality worldwide and is a major cause of long-term disability in people in both developed and developing countries [1, 2]. Middle cerebral artery occlusion (MCAO) is the most common cause of ischemic stroke and still results in high death rates of 40% to 80% [3]. Ischemic stroke causes a reduction in blood flow that is sufficient to alter normal cellular function. The incidence of post-reperfusion pronounced lesion oxidation occurs because of large amounts of reactive oxygen species (ROS), leading to apoptosis and an inflammatory response, which are frequently associated with a blood brain barrier (BBB) disruption, followed by brain edema [4, 5]. Following cerebral ischemia/reperfusion (I/R), inflammation causes the infiltration of peripheral inflammatory cells, the activation of microglia, and the over-generation of inflammatory mediators, such as cytokines, chemokines, and matrix metalloproteases (MMPs), which are tightly modulated by nuclear factor-kB (NF-κB). The cells maintain redox homeostasis by regulating oxidative stress through the induction of phase II antioxidant enzymes, such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), γ-glutamylcysteine synthase (γ-GCLC), superoxide dismutase (SOD), and catalase (CAT), which are regulated by the nuclear factor erythroid 2-related factor-2 (Nrf2) signaling [6, 7]
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