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.

This study investigated the effect of dihydrocapsaicin (DHC) on cerebral and blood brain barrier (BBB) damage in cerebral ischemia and reperfusion (I/R) models. The models were induced by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. The rats were divided into five groups: sham, or control group; vehicle group; and 2.5 mg/kg, 5 mg/kg, and 10 mg/kg BW DHC-treated I/R groups. After 24 h of reperfusion, we found that DHC significantly reduced the area of infarction, morphology changes in the neuronal cells including apoptotic cell death, and also decreased the BBB damage via reducing Evan Blue leakage, water content, and ultrastructure changes, in addition to increasing the tight junction (TJ) protein expression. DHC also activated nuclear-related factor-2 (Nrf2) which involves antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (GPx), and significantly decreased oxidative stress and inflammation via down-regulated reactive oxygen species (ROS), NADPH oxidase (NOX2, NOX4), nuclear factor kappa-beta (NF-ĸB), and nitric oxide (NO), including matrix metalloproteinases-9 (MMP-9) levels. DHC protected the cerebral and the BBB from I/R injury via attenuation of oxidative stress and inflammation. Therefore, this study offers to aid future development for protection against cerebral I/R injury in humans.

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Methamphetamine (METH) is known as a toxin for neuronal and glial cells. Previous studies have found that METH-induced glial cell death and inflammation is mediated by oxidative stress. However, the exact mechanisms of the inflammatory response remain unclear. Therefore, we hypothesized that the activation of nuclear factor-κB (NF-κB) signaling, a key mediator of inflammation, and the inhibition of nuclear factor erythroid 2-related factor-2 (Nrf2) signaling, a regulator of the antioxidant response, would be significant events occurring in response to METH-induced inflammation in a rat glioma cell line (C6 cells). Our results show that METH increased the production of nitric oxide (NO) and up-regulated the expression of its main regulatory protein, inducible nitric oxide synthase (iNOS). METH also induced NF-κB activation by increasing inhibitory κBα (IκBα) degradation and translocation of the NF-κB (p65) subunit into the nucleus. Additionally, METH inhibited the activation of the Nrf2 pathway by decreasing the translocation of Nrf2 into the nucleus and also by suppressing the expression of heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), and glutamate-cysteine ligase catalytic subunit (γ-GCLC), resulting in the suppression of superoxide dismutase (SOD) activity. Pretreatment with melatonin effectively promoted Nrf2 activation and reversed the METH-induced NF-κB response. Melatonin increased the expression of HO-1, NQO-1, and γ-GCLC, resulting in increased SOD activity. In addition, melatonin also decreased IκBα degradation, translocation of the p65 subunit, and expression of iNOS, resulting in decreased NO production. Taken together, our results indicate that melatonin diminishes the proinflammatory mediator in METH-stimulated C6 cells by inhibiting NF-κB activation and inducing Nrf2-mediated HO-1, NQO-1, and γ-GCLC expression.

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HHC together with 5-FU exerts a synergistic effect and may prove chemotherapeutically useful in treating human colon cancer.

Methamphetamine (METH) is a highly addictive drug causing neurodegenerative diseases. METH has been known to be neurotoxic by inducing oxidative stress, free radical, and pro-inflammatory cytokines. Previous studies have shown that METH could induce neuron and glial cell death, especially inducing glial cell-mediated neurotoxicity that plays a critical role in stress-induced central nervous system damage. Therefore, the aim of the present study is to explore the mechanisms of METH-induced cell death in the glial cell. METH-induced glial cells death is mediated via mitochondrial damage pathway. METH activates the upregulation of the Bax, cytochrome c, cleavage caspase 9 and 3 proteins, and downregulation of Bcl-XL protein in cascade. Pretreatment with melatonin, a neurohormone secreted by the pineal gland, effectively reduced glial cell death. Moreover, melatonin increased the Bcl-XL/Bax ratio but reduced the level of cytochrome c, cleavage caspase 9 and 3 proteins. Therefore, these results demonstrated that melatonin could reduce the cytotoxic effect of METH by decreasing the mitochondrial death pathway activation in glial cells. This outcome suggests that melatonin might be beneficial as the neuroprotection in neurodegenerative diseases caused by METH or other pathogens.

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