isoquercitrin and Reperfusion-Injury

This study aims to investigate whether isoquercitrin (Iso) exerts a neuroprotective role effect after cerebral ischemia-reperfusion (CIR) via up-regulating neuroglobin (Ngb) or reducing oxidative stress.. The middle cerebral artery occlusion/reperfusion (MCAO/R) model was constructed using Sprague Dawley rats. First, we divided 40 mice into 5 groups (n = 8): sham, MCAO/R, Low-dosed Iso (5 mg/kg Iso), Mid-dosed Iso (10 mg/kg Iso), and High-dosed Iso (20 mg/kg Iso). Then, 48 rats were separated into 6 groups (n = 8): sham, MCAO/R, Iso, artificial cerebrospinal fluid, Ngb antisense oligodeoxynucleotides (AS-ODNs), and AS-ODNs ± Iso. The effects of Iso on brain tissue injury and oxidative stress were evaluated using hematoxylin-eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunofluorescence, western blotting, and real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and reactive oxygen species (ROS) detection.. The neurologic score, infarct volume, histopathology, apoptosis rate, and ROS production were reduced in Iso dose-dependent. The Ngb expression enhanced in Iso dose-dependent. The oxidative stress-related factors SOD, GSH, CAT, Nrf2, HO-1, and HIF-1α levels also increased in Iso dose-dependent, whereas the MDA levels decreased. However, related regulation of Iso on brain tissue damage and oxidative stress were reversed after low expression of Ngb.. Isoquercitrin played a neuroprotective role after CIR through up-regulating of Ngb and anti-oxidative stress.

Topics: Animals; Apoptosis; Brain Ischemia; Mice; Neuroglobin; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion; Reperfusion Injury

Renal ischemia-reperfusion injury (RIRI) occurs after several surgical procedures such as kidney transplantation and partial nephrectomy. Isoquercitrin (IQ) exhibited protective effects in cerebral ischemia-reperfusion injury. In the present study, we aimed to evaluate the effects of IQ on the prevention of RIRI. The mouse model of RIRI was induced by 30-minute clamping of the left renal pedicle after excising of the right kidney, followed by 24-hour reperfusion. Thirty mice were randomly divided into the following 3 groups: sham operation, RIRI model group, and IQ pretreatment + RIRI. Serum creatinine and blood urea nitrogen (BUN) were used for evaluating renal function. Kidney cell apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Moreover, the pro-inflammatory cytokines (TNF-α, IL-6), the oxidative stress associated factors (malondialdehyde, superoxide dismutase), and the apoptotic factors (Bcl-2, Bax) were assessed. After RIRI, BUN, creatinine, TNF-α, IL-6, malondialdehyde, and Bax were significantly increased, and levels of superoxide dismutase and Bcl-2/Bax ratio and Bcl-2 expression were decreased markedly. As expect, IQ reversed these changes. These data indicate that IQ plays a protective role during RIRI, which may be partially mediated through the actions of antioxidation, anti-inflammation, and antiapoptosis.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Quercetin; Reperfusion Injury

Isoquercetin (Iso) has been found to have neuroprotective effects against cerebral ischemic stroke. However, the exact molecular mechanism underlying its neuroprotective ability remains unclear. In this study, we aimed to evaluate the neuroprotective effects of Iso in primary culture of rat hippocampal neurons exposed to oxygen and glucose deprivation and reperfusion (OGD/R) injury and in rats subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) injury. We found that rats treated with Iso exhibited a lower degree of infarct volume, and brain water content than the vehicle-treated rats. Treatment with Iso also improved the neurological deficits in MCAO/R rats as shown by the decreased modified neurological severity score. Iso treatment decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) production, and increased the activity of superoxide dismutase (SOD) and catalase (CAT) in brains of MCAO/R rats and primary culture of rat hippocampal neurons exposed to OGD/R. Iso treatment prevents I/R-induced neuronal apoptosis in vivo and in vitro as indicated by increased cell viability and decreased number of TUNEL-positive cells, accompanying with downregulation of cleaved caspase-3 protein and upregulation of Bcl-2 protein. Moreover, Nrf2 knockdown weakened the anti-apoptotic and anti-oxidant activities of Iso in primary culture of rat hippocampal neurons exposed to OGD/R. Interestingly, we found that Iso could induce Nrf2 translocation from cytoplasm to nucleus in primary culture of rat hippocampal neurons exposed to OGD/R. Iso activated the NOX4/ROS/NF-κB signaling pathway in in vivo and in vitro cerebral I/R injury models. Nrf2 knockdown blocked the inhibitory effect of Iso on protein expression of NOX4, p-IκBα and p-p65 in primary culture of rat hippocampal neurons exposed to OGD/R. All the data suggested that Iso protected against oxidative stress and neuronal apoptosis in in vivo and in vitro cerebral I/R injury models via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB signaling pathway. Our findings suggested that Iso could be a potential agent for I/R brain injury.

Topics: Animals; Apoptosis; Cells, Cultured; Infarction, Middle Cerebral Artery; Male; NADPH Oxidase 4; Neuroprotective Agents; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Quercetin; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; RNA Interference; Signal Transduction; Up-Regulation

Ischemic stroke is a major disability and cause of death worldwide due to its narrow therapeutic time window. Neuroprotective agent is a promising strategy to salvage acutely ischemic brain tissue and extend the therapeutic time window for stroke treatment. In this study, we aimed to evaluate the neuroprotective effects of isoquercetin in (1) primary culture of rat hippocampal neurons exposure on oxygen and glucose deprivation and reperfusion (OGD/R) injury and (2) rats subjected to transient middle cerebral artery occlusion and reperfusion (MCAO/R) injury. The results showed that isoquercetin post-treatment reduced the infarct size, number of apoptotic cells, oxidative stress, and inflammatory response after ischemia and reperfusion injury. The underlying mechanism study indicated that the neuroprotective effects of isoquercetin were elicited via suppressing the activation of toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB) and caspase-1; the phosphorylation of ERK1/2, JNK1/2, and p38 mitogen-activated protein kinase (MAPK); and the secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6. In addition, isoquercetin also effectively alleviated hippocampus neuron apoptosis by regulation of cyclic AMP responsive element-binding protein (CREB), Bax, Bcl-2, and caspase-3. Our report provided new considerations into the therapeutic action and the underlying mechanisms of isoquercetin to improve brain injury in individuals who have suffered from ischemic stroke. As a potent anti-inflammatory and anti-oxidative compound with neuroprotective capacities, the beneficial effects of isoquercetin when used to treat ischemic stroke and related diseases in humans warrant further studies.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Brain Ischemia; CA1 Region, Hippocampal; Cells, Cultured; Inflammation; Ischemia; Male; Neurons; Neuroprotective Agents; Oxidative Stress; Quercetin; Rats, Sprague-Dawley; Reperfusion Injury