baohuoside-i and Brain-Ischemia

Astrocytic nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a potential therapeutic target of ischaemic preconditioning (IPC). Icariside II (ICS II) is a naturally occurring flavonoid derived from Herba Epimedii with Nrf2 induction potency. This study was designed to clarify if exposure to ICS II mimicks IPC neuroprotection and if Nrf2 from astrocytes contributes to ICS II preconditioning against ischaemic stroke.. Mice with transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischaemia and primary astrocytes challenged with oxygen-glucose deprivation (OGD) were used to explore the neuroprotective effect of ICS II preconditioning. Additionally, Nrf2-deficient mice were pretreated with ICS II to determine whether ICS II exerts its neuroprotection by activating Nrf2.. ICS II pretreatment mitigated cerebral injury in the mouse model of ischaemic stroke along with improving long-term recovery. Furthermore, proteomics screening identified Nrf2 as a crucial gene evoked by ICS II treatment and required for the anti-oxidative effect and anti-inflammatory effect of ICS II. Also, ICS II directly bound to Nrf2 and reinforced the transcriptional activity of Nrf2 after MCAO. Moreover, ICS II pretreatment exerted cytoprotective effects on astrocyte cultures following lethal OGD exposure, by promoting Nrf2 nuclear translocation and activating the OXPHOS/NF-κB/ferroptosis axis, while neuroprotection was decreased in Nrf2-deficient mice and Nrf2 siRNA blocked effects of ICS II.. ICS II preconditioning provides robust neuroprotection against ischaemic stroke via the astrocytic Nrf2-mediated OXPHOS/NF-κB/ferroptosis axis. Thus, ICS II could be a promising Nrf2 activator to treat ischaemic stroke.

Topics: Animals; Brain Ischemia; Ferroptosis; Flavonoids; Ischemic Stroke; Mice; Neuroprotection; Neuroprotective Agents; NF-E2-Related Factor 2; NF-kappa B; Signal Transduction; Stroke

Cerebral ischaemia/reperfusion causes exacerbated neuronal damage involving excessive autophagy and neuronal loss. The present study was designed to investigate the effect of icariside II, one of main active ingredients of Herba Epimedii on this loss and whether this is related to its PDE 5 inhibitory action.. Focal cerebral ischaemia was induced in the rat by transient middle cerebral artery occlusion over 2 hr, followed by reperfusion with icariside II, 3-methylamphetamine or rapamycin. The effect of icariside II was determined measuring behaviour changes and the size of the infarction. The expressions of PDE 5, autophagy-related proteins and the level of phosphorylation of glycogen synthase kinase-3β (GSK-3β) were determined. Cultured primary cortical neurons were subjected to oxygen and glucose deprivation followed by reoxygenation in the presence and absence of icariside II. A surface plasmon resonance assay and molecular docking were used to explore the interactions of icariside II with PDE 5 or GSK-3β.. Icariside II not only protected against induced ischaemic reperfusion injury in rats but also attenuated such injury in primary cortical neurons. The neuroprotective effects of icariside II on such injury were attributed to interfering with the PKG/GSK-3β/autophagy axis by directly bounding to PDE 5 and GSK-3β.. These findings indicate that icariside II attenuates cerebral I/R-induced injury via interfering with PKG/GSK-3β/autophagy axis. This study raises the possibility that icariside II and other PDE 5 inhibitors maybe effective in the treatment ischaemia stroke.

Topics: Animals; Autophagy; Brain Ischemia; Flavonoids; Glycogen Synthase Kinase 3 beta; Molecular Docking Simulation; Phosphodiesterase 5 Inhibitors; Rats; Reperfusion Injury

Cerebral ischemia/reperfusion (I/R) results in harmful consequences during ischemic stroke, especially the disruption of the blood-brain barrier (BBB), which leads to severe hemorrhagic transformation through aggravation of edema and brain hemorrhage. Our previous study demonstrated that icariside II (ICS II), which is derived from Herba Epimedii, attenuates cerebral I/R injury by inhibiting the GSK-3β-mediated activation of autophagy both in vitro and in vivo. However, the effect of ICS II on the BBB remains unclear. Thus, in this study, we investigated the regulation of BBB integrity by ICS II after cerebral I/R injury and further explored the underlying mechanism in rats. Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO), and the treatment groups were administered ICS II at a dose of 16 mg/kg by gavage twice a day for 3 days. The results showed that ICS II effectively prevented BBB disruption, as evidenced by Evans Blue staining. Moreover, ICS II not only significantly reduced the expression of MMP2/9 but also increased TIMP1 and tight junction protein (occludin, claudin 5, and ZO 1) expression. Intriguingly, ICS II may directly bind to both MMP2 and MMP9, as evidenced by molecular docking. In addition, ICS II also inhibited cerebral I/R-induced apoptosis and ameliorated the Bax/Bcl-2 ratio and cleaved-caspase 3 level. Collectively, our findings reveal that ICS II significantly ameliorates I/R-induced BBB disruption and neuronal apoptosis in MCAO rats by regulating the MMP9/TIMP1 balance and inhibiting the caspase 3-dependent apoptosis pathway.

Topics: Animals; Apoptosis; Blood-Brain Barrier; Brain; Brain Ischemia; Claudin-5; Flavonoids; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Molecular Docking Simulation; Neurons; Neuroprotective Agents; Occludin; Protein Binding; Rats, Sprague-Dawley; Reperfusion Injury; Tissue Inhibitor of Metalloproteinase-1; Zonula Occludens-1 Protein

To investigate the effects of icariside II on brain tissue oxidative stress and Nrf2/HO-1 expression in rats with cerebral ischemia-reperfusion injury (CIRI).. One hundred SD rats were randomly divided into sham-operated, model, and 5, 10 and 20 mg/kg icariside II groups, 20 rats in each group. The middle cerebral artery occlusion model (ischemia for 2 h followed by reperfusion for 24 h) was established in the later 4 groups. In later 3 groups, at reperfusion beginning, the rats were intragastrically administrated with 5, 10 and 20 mg/kg icariside II, respectively. After 24 h of reperfusion, the neurological severity score, cerebral water content and cerebral infarction volume, brain tissue oxidative stress indexes and Nrf2 and HO-1 protein expressions were determined.. Compared with model group, in 20 mg/kg icariside II group the neurological severity score, cerebral water content and cerebral infarction volume, brain tissue ROS content and MDA level were significantly decreased (P<0.05), and the brain tissue SOD, GSH-Px and catalase levels and Nrf2 and HO-1 protein levels were significantly increased (P<0.05).. Icariside II can alleviate the CIRI in rats through reducing brain tissue oxidative stress and improving Nrf2/HO-1 expression.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Flavonoids; Male; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Severity of Illness Index

Icariside II (IRS) is a metabolite of icariin, which is derived from Herba Epimedii. Although the potential therapeutic effects of icariin on ischemic brain injury were well-investigated; the role of IRS in ischemic stroke is still not addressed clearly. Therefore, the current study aimed to evaluate the effects of IRS on cerebral ischemia-reperfusion injury in rats. The rats were pre-treated by IRS (10 or 30 mg kg(-1), twice a day) for 3 days. After pre-treatment, a MCAO (middle cerebral artery occlusion) for 2 h followed by reperfusion for 24 h was applied on the rats to induce the cerebral ischemia injury model. The neurological deficit scores were assessed at 24 h after reperfusion, then animals were sacrificed, infarct volumes were determined by 2,3,5-triphenyltetrazolium chlorid (TTC) staining and protein expression levels of interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), inhibitory κB (IκB), nuclear factor κB (NF-κB) p65, peroxisome proliferator-activated receptor α (PPARα), and peroxisome proliferator-activated receptor γ (PPARγ) were assayed by using Western blot. IRS pretreatment markedly improved the neurological dysfunction and decreased infarct volume in MCAO rats. In addition, IRS inhibited IL-1β and TGF-β1 protein expression, and resulted in beneficial effects such as inhibition of IκB-α degradation and NF-κB activation induced by MCAO, in a dose-dependent manner. Furthermore, IRS increased the protein expression levels of PPARα and PPARγ in the ischemic brain. In conclusion, pretreatment with IRS protects against cerebral ischemic/reperfusion injury via up-regulation of PPARα and PPARγ and inhibition of NF-κB activation.

Topics: Animals; Brain Ischemia; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Flavonoids; Male; Neuroprotective Agents; NF-kappa B; PPAR alpha; PPAR gamma; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Up-Regulation

the purpose of the present study was to examine the protective effect of Icariside II (IS) on cerebral microcirculatory disturbance and neuronal injury in hippocampal CA1 region induced by global cerebral I/R and the underlying mechanism.. male Mongolian gerbils (50-70 g) were subjected to bilateral common carotid arteries occlusion for 30 min and followed by reperfusion for 72 h. IS (20 mg/kg) was administered orally 2 h before ischemia and 6, 24, 48, 70 h after reperfusion. After 72 h of reperfusion, the leukocyte adhesion, albumin leakage, and velocity of RBC in the venules were determined with an upright microscope. Neuronal injury in hippocampal CA1 region was assessed by Nissl staining and the in situ TUNEL assay. Bax, Bcl-2, and cleaved caspase-3 proteins were detected by Western blot, and MDA content and complex I activity by ELISA assay in hippocampus.. IS inhibited I/R-elicited leukocyte adhesion, albumin leakage and increased the velocity of RBC in cerebral venules. IS down-regulated Bax and cleaved caspase-3 expression, up-regulated Bcl-2 expression of hippocampus and decreased the number of TUNEL positive neurons and the neuronal loss induced by I/R in hippocampal CA1 region. In addition, IS could increase the activity of complex I and decrease the production of MDA after I/R.. IS could alleviate the microcirculatory disturbance and neuronal injury in hippocampal CA1 region induced by global cerebral I/R, which might involve regulating complex I activity.

Topics: Animals; Brain; Brain Ischemia; CA1 Region, Hippocampal; Carotid Artery, Common; Cerebrovascular Circulation; Flavonoids; Gerbillinae; Male; Microcirculation; Neuroprotective Agents; Reperfusion Injury; Time Factors