Effects of isosakuranetin on cerebral infarction and blood brain barrier damage from cerebral ischemia/reperfusion injury in a rat model.

This study investigated the effects of isosakuranetin (5,7-dihydroxy-4'-methoxyflavanone) on cerebral infarction and blood brain barrier (BBB) damage in cerebral ischemia and reperfusion (I/R) in a rat model. The right middle cerebral artery was occluded for 2 h followed by reperfusion. The experimental rats were divided into five groups: a sham, or control group; vehicle group; and 5 mg/kg, 10 mg/kg, and 20 mg/kg bodyweight isosakuranetin-treated I/R groups. After 24 h of reperfusion, the rats were tested using a six-point neurological function score. The percentage of cerebral infarction was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining. BBB leakage was determined by Evan Blue injection assay and brain morphology changes were observed under light microscopy following staining with hematoxylin and eosin (H&E). The results of neurological function score revealed that isosakuranetin reduced the severity of neurological damage. A dose of 10 and 20 mg/kg bodyweight of isosakuranetin significantly decreased the infarct volume. All three doses of isosakuranetin significantly decreased Evan Blue leakage. The penumbra area of the I/R brains revealed the characteristics of apoptotic cell death. Therefore, isosakuranetin-treated I/R attenuated the brain damage from cerebral I/R injury and further investigation of the mechanisms warrant further investigation to assist in the development of protective strategies against cerebral I/R injury in clinical trials.Communicated by Ramaswamy H. Sarma.

Dihydrocapsaicin-induced angiogenesis and improved functional recovery after cerebral ischemia and reperfusion in a rat model.

This study investigated the long-term effects of dihydrocapsaicin (DHC)-induced angiogenesis and improved functional outcomes in cerebral ischemia and reperfusion (I/R) rats. Middle cerebral artery occlusion was induced in I/R rats for 2 h, followed by reperfusion. The animals were divided into three groups: sham, I/R + vehicle, and I/R + DHC (10 mg/kg body weight). Fourteen days after I/R injury, the DHC-treated I/R rats had decreased neurological deficit scores, infarct volume, and brain morphology changes. DHC-induced angiogenesis significantly increased the expression of angiogenic factor proteins, such as hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and matrix metalloprotease 9 (MMP-9), at 3 d and 14 d following I/R and also increased the expression of angiogenic inhibitors, such as angiopoietin 1 (Ang-1) and its receptor tyrosine kinase (Tie-2), at 14 d following reperfusion. DHC-mediated angiogenesis was confirmed by a significant increase in positive BrdU labeling that co-localized with the von Willebrand factor (an endothelial cell marker) at 14 d after I/R. Furthermore, rotarod and pole tests demonstrated that DHC promoted functional recovery when compared with the vehicle group. Thus, the results reveal that DHC mediates angiogenesis and functional recovery after an ischemic stroke.

Hexahydrocurcumin alleviated blood-brain barrier dysfunction in cerebral ischemia/reperfusion rats.

BACKGROUND: Hexahydrocurcumin (HHC), a major metabolite of curcumin, has been reported to have protective effects against ischemic and reperfusion damage. The goal of the present research was to examine whether HHC could alleviate brain damage and ameliorate functional outcomes by diminishing the blood-brain barrier (BBB) damage that follows cerebral ischemia/reperfusion. METHODS: Middle cerebral artery occlusion was induced for 2 h in rats followed by reperfusion. The rats were divided into three groups: sham-operated, vehicle-treated, and HHC-treated groups. At the onset of reperfusion, the rats were immediately intraperitoneally injected with 40 mg/kg HHC. At 48 h after reperfusion, the rats were evaluated for neurological deficits and TTC staining. At 24 h and 48 h after reperfusion, animals were sacrificed, and their brains were extracted. RESULTS: Treatment with HHC reduced neurological scores, infarct volume, morphological changes, Evans blue leakage and immunoglobulin G extravasation. Moreover, HHC treatment reduced BBB damage and neutrophil infiltration, downregulated myeloperoxidase, ICAM-1, and VCAM-1, upregulated tight junction proteins (TJPs), and reduced aquaporin 4 expression and brain water content. CONCLUSION: These results revealed that HHC treatment preserved the BBB from cerebral ischemia/reperfusion injury by regulating TJPs, attenuating neutrophil infiltration, and reducing brain edema formation.

Hexahydrocurcumin protects against cerebral ischemia/reperfusion injury, attenuates inflammation, and improves antioxidant defenses in a rat stroke model.

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.

Dihydrocapsaicin Attenuates Blood Brain Barrier and Cerebral Damage in Focal Cerebral Ischemia/Reperfusion via Oxidative Stress and Inflammatory.

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.

Suppression effects of O-demethyldemethoxycurcumin on thapsigargin triggered on endoplasmic reticulum stress in SK-N-SH cells.

Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Therefore, interventions that attenuate ER stress may contribute to induction in apoptotic cell death. This study aimed to evaluate the potential involvement of O-demethyldemethoxycurcumin, an analog of curcuminoids, on thapsigargin-induced apoptosis in cultured neuroblastoma (SK-N-SH) cells through the ER stress signaling pathway. The results showed that O-demethyldemethoxycurcumin reduced thapsigargin induced cell death in SK-N-SH cells and the release of lactate dehydrogenase (LDH) by decreasing the apoptotic cell death induced by thapsigargin. Consistent with these findings, O-demethyldemethoxycurcumin inhibited the thapsigargin-induced activation of cleavagecaspase-12. Moreover, O-demethyldemethoxycurcumin attenuated the intracellular Ca(2+) level and the expression of the calpain protein. O-demethyldemethoxycurcumin also downregulated the expression of ER stress signaling proteins, including the phosphorylation of PKR-like endoplasmic reticulum kinase (p-PERK), the phosphorylation of inositol-requiring enzyme 1 (p-IRE1), activating transcription factor 6 (ATF6), binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP). Our findings suggest that O-demethyldemethoxycurcumin could protect against thapsigargin-induced ER stress in SK-N-SH cells.