stilbenes and Brain-Edema

Early brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms.. A total of 299 male Sprague-Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood-brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI.. We found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 ± 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices.. These results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment.

Topics: Adenine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Blood-Brain Barrier; Brain Edema; Carrier Proteins; Cell Cycle Proteins; Encephalitis; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Gene Expression Regulation; Indoles; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Small Interfering; Signal Transduction; Stilbenes; Subarachnoid Hemorrhage; Sulfonamides; Thiophenes

Early brain injury is considered to be a major risk that is related to the prognosis of subarachnoid hemorrhage (SAH). In SAH model rats, brain edema and apoptosis have been closely related with death rate and neurological function. Sirtuin 1 (SIRT1) was reported to be involved in apoptosis in cerebral ischemia and brain tumor formation through p53 deacetylation. The present study aimed to evaluate the role of SIRT1 in a rat endovascular perforation model of SAH. The SIRT1 activator resveratrol (RES) was administered 48 h prior to SAH induction and the SIRT1 inhibitor Sirtinol (SIR) was used to reverse the effects of RES on SIRT1 expression. Mortality rate, neurological function and brain water content were measured 24 h post‑SAH induction. Proteins associated with the blood brain barrier (BBB), apoptosis and SIRT1 in the cortex, such as zona occludens 1 (ZO‑1), occludin, claudin‑5, SIRT1, p53 and cleaved caspase3 were investigated. mRNA expression of the p53 downstream molecules including Bcl‑associated X protein, P53 upregulated modulator of apoptosis, Noxa and BH3 interacting‑domain death agonist were also investigated. Neuronal apoptosis was also investigated by immunofluorescence. RES pretreatment reduced the mortality rate and improved neurological function, which was consistent with reduced brain water content and neuronal apoptosis; these effects were partially reversed by co‑treatment with SIR. SIRT1 may reduce the brain water content by improvement of dysfunctional BBB permeability, and protein analysis revealed that both ZO‑1, occludin and claudin‑5 may be involved, and these effects were reversed by SIRT1 inhibition. SIRT1 may also affect apoptosis post‑SAH through p53 deacetylation, and the analysis of p53 related downstream pro‑apoptotic molecules supported this hypothesis. Localization of neuron specific apoptosis revealed that SIRT1 may regulate neuronal apoptosis following SAH. SIRT1 may also ease brain edema and neuronal protection through BBB improvement and p53 deacetylation. SIRT1 activators such as RES may have the potential to improve the prognosis of patients with SAH and clinical research should be investigated further.

Topics: Animals; Apoptosis; Brain Edema; Caspase 3; Disease Models, Animal; Fluorescent Antibody Technique; Male; Mortality; Neurons; Neuroprotection; Occludin; Rats; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes; Subarachnoid Hemorrhage; Zonula Occludens-1 Protein

Ischemia reperfusion (IR) injury (IRI) is harmful to the cerebral system and causes mitochondrial oxidative stress. The antioxidant response element (ARE)-mediated antioxidant pathway plays an important role in maintaining the redox status of the brain. Heme oxygenase-1 (HO-1), combined with potent AREs in the promoter of HO-1, is a highly effective therapeutic target for protection against cerebral IRI. Pterostilbene (PTE), a natural dimethylated analog of resveratrol from blueberries, is a strong natural antioxidant. PTE has been shown to be beneficial for some nervous system diseases and may regulate HO-1 signaling. This study was designed to investigate the protective effects of PTE on cerebral IRI and to elucidate potential mechanisms underlying those effects. Mouse brains and cultured HT22 neuron cells were subjected to IRI. Prior to this procedure, the brains or cells were exposed to PTE in the absence or presence of the HO-1 inhibitor ZnPP or HO-1 small interfering RNA (siRNA). PTE conferred a cerebral protective effect, as shown by increased neurological scores, viable neurons and decreased brain edema as well as a decreased ion content and apoptotic ratio in vivo. PTE also increased the cell viability and decreased the lactate dehydrogenase (LDH) leakage and apoptotic ratio in vitro. ZnPP and HO-1 siRNA both blocked PTE-mediated cerebral protection by inhibiting HO-1 signaling and further inhibited two HO-1 signaling-related antioxidant molecules:. quinone oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTs), which are induced by PTE. PTE also promoted a well-preserved mitochondrial membrane potential (MMP), mitochondria complex I activity, and mitochondria complex IV activity, increased the mitochondrial cytochrome c level, and decreased the cytosolic cytochrome c level. However, this PTE-elevated mitochondrial function was reversed by ZnPP or HO-1 siRNA treatment. In summary, our results demonstrate that PTE treatment attenuates cerebral IRI by reducing IR-induced mitochondrial oxidative damage through the activation of HO-1 signaling.

Topics: Animals; Apoptosis; Brain; Brain Edema; Brain Ischemia; Cell Line; Cell Survival; Glutathione Transferase; Heme Oxygenase-1; Ions; L-Lactate Dehydrogenase; Male; Mice, Inbred C57BL; Mitochondria; NAD(P)H Dehydrogenase (Quinone); Neurons; Oxidative Stress; Protoporphyrins; Reperfusion Injury; RNA, Small Interfering; Signal Transduction; Stilbenes

Both resveratrol (RV) and enriched environment (EE) exert beneficial effects on neurological functional recovery after an ischemic brain injury.. The neuroprotective effect of combined treatment of RV and EE was examined in a rat model of middle cerebral artery occlusion (MCAO), aiming to further promote neurological functional recovery.. The combined therapy of RV and EE clearly improved locomotor activity and behaviour examination, compared to the monotherapy of RV or EE alone. Stroke severity was also markedly ameliorated by the co-treatment. Mechanistic study revealed that the combined treatment reduced oxidative stress. Moreover, the detrimental ERK1/2 signalling upregulated by MCAO injury was markedly suppressed by the co-treatment, compared to RV or EE monotherapy.. Altogether, the combined therapy of RV and EE showed a clearly enhanced neuroprotective effect, compared to RV or EE monotherapy, which might be a new strategy for the treatment of ischemic brain injury.

Topics: Analysis of Variance; Animals; Brain Edema; Brain Infarction; Brain Injuries; Disease Models, Animal; Environment; Hydrogen Peroxide; Infarction, Middle Cerebral Artery; Locomotion; Male; MAP Kinase Signaling System; Neurologic Examination; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes

Neonatal hypoxic-ischemic (HI) brain damage causes acute mortality and morbidity in newborns and long-term neurological disorders in the survivors. Pterostilbene (PTE) is a natural compound possessing various biological and pharmacological activities. In the present study, we aimed to investigate the effect of PTE on neonatal HI brain damagein P7 rat model and to explore the possible mechanisms. Neonatal HI brain damage was induced in rat pups (P7). Prior to the induction of HI injury, PTE was injected with or without zinc protoporphyrin IX (ZnPP), an inhibitor of heme oxygenase-1 (HO-1). ZnPP was used to test whether abnormal changes of HO-1 expression were involved in the effect of PTE. The results showed that PTE exhibited excellent neuroprotective effects against neonatal HI brain injury, as evidenced by the decrease of brain infarct volume, brain edema, neurological score, and improvement in motor coordination motor deficit and working memory deficit. PTE pretreatment decreased the expression of several proinflammatory cytokines, including TNFα, IL-1β, IL-6, and key transcription factor p65 NF-κB, and reduced the number of TUNEL-stained neurons, indicating the inhibition of inflammation and programmed cell death. Moreover, PTE pretreatment decreased thiobarbituric acid reactive substances content, increased superoxide dismutase activity and decreased reactive oxygen species level, indicating that PTE played an important antioxidant role. Furthermore, ZnPP was able to inhibit PTE-induced suppression of oxidative stress, programmed cell death, inflammation and brain damage. In conclusion, PTE pretreatment prevented HI-induced brain injury in newborns through HO-1-mediated reduction of oxidative stress, programmed cell death, and inflammation, and final improvement of histological and functional injury. Overall, the data that obtained in rat model provide novel insights into the pathogenesis of neonatal HI brain injury and may be translational to human clinical intervention for HI-associated brain injury in newborns.

Topics: Animals; Animals, Newborn; Brain; Brain Edema; Brain Injuries; Cell Death; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Female; Gait Disorders, Neurologic; Heme Oxygenase (Decyclizing); Hypoxia-Ischemia, Brain; Male; Memory Disorders; Neuroprotective Agents; Oxidative Stress; Protoporphyrins; Psychomotor Disorders; Rats; Stilbenes; Up-Regulation

To study the effect of resveratrol on cerebral infarct volume, cerebral edema as well as the expression of nuclear fac for (NF-kappaB) p65 in the experimental permanent middle cerebral artery occlusion.. A middle cerebral artery occlusion model was constructed in 20 Wistar rats with Longa's method. Then the 20 rats were divided into 4 groups: control group, and 3 resveratrol groups (resveratrol of the concentrations of 10(-8) g/kg, 10(-7) g/kg, and 10(-6) g/kg were injected intravenously) (group 1- 4). The area of infarct was examined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The water content was calculated by dry and wet weight method. The expression of NF-kappaB p65 was investigated with immunohistochemistry.. The ischemic volume was 241 +/- 36, 222 +/- 39, 126 +/- 16, and 128 +/- 19 * in the groups 1 - 4 respectively, and the volume ratio was 0.49 +/- 0.04, 0.47 +/- 0.04, 27 +/- 0.02, and 0.43 +/- 0.02 respectively. The brain water content was 83.5% +/- 1.5%, 82.9% +/- 1.4%, 79.5% +/- 1.5%, and 79.9% +/- 1.4% in groups 1 - 4 with a significant difference between 10(-7) g/kg resveratrol group and pure ischemia group and 10(-6) g/kg resveratrol group and pure ischemia group (both P < 0.05). NF-kappaB p65 was not expressed in the normal control group and sham operation group, and was expressed 2 hours after pure ischemia. The expression of NF-kappaB p65 positive cells was the most significant 12 hours after the pure ischemia and began to decrease 24 hours after ischemia.. Resveratrol has a neuroprotective effect on the ischemic brain. This effect is related to the inhabitation of expression of NF-kappaB p65.

Topics: Animals; Brain Edema; Brain Ischemia; Male; Neuroprotective Agents; NF-kappa B; Rats; Rats, Wistar; Resveratrol; Stilbenes; Transcription Factor RelA