notoginsenoside-r1 and Infarction--Middle-Cerebral-Artery

Due to sudden loss of cerebral blood circulation, acute ischemic stroke (IS) causes neuronal energy attenuation or even exhaustion by mitochondrial dysfunction resulting in aggravation of neurological injury. In this study, we investigated if Notoginsenoside R1 ameliorated cerebral energy metabolism by limiting neuronal mitochondrial dysfunction in acute IS. Male Sprague-Dawley rats (260-280 g) were selected and performed by permanent middle cerebral artery occlusion model. In vitro, the oxygen glucose deprivation (OGD) model of Neuro2a (N2a) cells was established. We found Notoginsenoside R1 treatment reduced rats' cerebral infarct volume and neurological deficits, with increased Adenosine triphosphate (ATP) level together with upregulated expression of glucose transporter 1/3, monocarboxylate transporter 1 and citrate synthase in brain peri-ischemic tissue. In vitro, OGD-induced N2a cell death was inhibited, cell mitochondrial morphology was improved. Mitochondrial amount, mitochondrial membrane potential, and mitochondrial DNA copy number were increased by Notoginsenoside R1 administration. Furthermore, mitochondrial energy metabolism-related mRNA array found Atp12a and Atp6v1g3 gene expression were upregulated more than twofold, which were also verified in rat ischemic tissue by quantitative polymerase chain reaction (qPCR) assay. Therefore, Notoginsenoside R1 administration increases cerebral glucose and lactate transportation and ATP levels, ameliorates neuronal mitochondrial function after IS. Notoginsenoside R1 may be a novel protective agent for neuronal mitochondria poststroke.

Topics: Adenosine Triphosphate; Animals; Brain Ischemia; Ginsenosides; Glucose; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Mitochondria; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

The leakage of blood-brain barrier (BBB) is main pathophysiological change in acute stage of ischemic stroke, which not only deteriorates neurological function, but also increases the risk of hemorrhagic transformation after thrombolysis.. This article investigates the efficacy of Notoginsenoside R1, an active ingredient of Panax notoginseng, on BBB permeability and explores related mechanisms after acute ischemic stroke.. In vivo, male Sprague-Dawley rats (260-280 g) were selected and randomly divided into 6 groups: sham group, model group, low, middle and high doses of Notoginsenoside R1 groups and positive drug Dl-3-n-Butylphthalide group. Except for sham group, rats were performed with permanent middle cerebral artery occlusion model in each group. Twelve hours later, rats were evaluated for Bederson neurological function, and BBB integrity by Evans blue leak imaging; Triphenyltetrazolium chloride staining was used to detect the volume of cerebral infarction. Frozen sections of rats' brain tissue were prepared for detection of MMPs activity in situ zymography. Peripheral tissue of cerebral infarction was collected and tested the expression of MMP2, 9 and tight junction proteins (zo1, claudin5, occludin) by western blot. In vitro, transwell endothelial barrier model was established by bEnd.3 cells. Oxygen glucose deprivation (OGD) was chosen to simulate the hypoxic environment. Suitable OGD stimulation time as well as Notoginsenoside R1 and Dl-3-n-Butylphthalide optimal dose concentrations were determined through transwell leakage and CCK8 assay. Furthermore, endothelial subcellular component proteins were extracted. The change of zo1, claudin5, occludin and caveolin1 was detected by western blot.. Notoginsenoside R1 treatment significantly reduced BBB leakage and cerebral infarction volume, weakened neurological deficits in post-stroke rats. Moreover, it inhibited the activity of MMPs in infarcted cortex and striatum, down-regulated MMP2, 9 and up-regulated zo1 and claudin5 expressions in penumbra. In vitro, Notoginsenoside R1 treatment decreased OGD-induced endothelial barrier permeability, restored expressions of zo1, claudin5 on cellular membrane and cytoplasm, as well as mediated membrane redistribution of occludin and caveolin1 from actin cytoskeletal fraction.. Notoginsenoside R1 treatment attenuates BBB permeability, cerebral infarction volume and neurological impairments in rats with acute cerebral ischemia. The mechanisms might be related to intervening degradation and redistribution of zo1, caludin5 and occludin by caveolin1/ MMP2/9 pathway. More effects and mechanisms of Notoginsenoside R1 on rehabilitation of stroke are worthy to be explored in the future.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Caveolin 1; Ginsenosides; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Permeability; Rats; Rats, Sprague-Dawley; Tight Junctions

Ischemic stroke is a syndrome of severe neurological responses that cause neuronal death, damage to the neurovascular unit and inflammation. Notoginsenoside R1 (NG-R1) is a neuroprotective drug that is commonly used to treat neurodegenerative and cerebrovascular diseases. However, its potential mechanisms on the regulation of small molecule metabolism in ischemic stroke are largely unknown. The aim of this study was to explore the potential mechanisms of NG-R1 on the regulation of small molecule metabolism after ischemic stroke. Here, we found that NG-R1 reduced infarct size and improved neurological deficits by ameliorating neuronal damage and inhibiting glial activation in MCAO/R rats. Furthermore, using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), we clarified that NG-R1 regulated ATP metabolism, the tricarboxylic acid (TCA) cycle, the malate-aspartate shuttle, antioxidant activity, and the homeostasis of iron and phospholipids in the striatum and hippocampus of middle cerebral artery occlusion/reperfusion (MCAO/R) rats. In general, NG-R1 is a promising compound for brain protection from ischemic/reperfusion injury, possibly through the regulation of brain small molecule metabolism.

Topics: Animals; Apoptosis; Brain; Disease Models, Animal; Energy Metabolism; Ginsenosides; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Neuroprotective Agents; Predictive Value of Tests; Rats, Sprague-Dawley; Reperfusion Injury; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Time Factors

Naodesheng (NDS) is a widely used traditional Chinese medicine (TCM) prescription for the treatment of ischemic stroke. A combination of 10 components is derived from NDS. They are: Notoginsenoside R1, ginsenoside Rg1, ginsenoside b1, ginsenoside Rd, hydroxysafflor yellow A, senkyunolide I, puerarin, daidzein, vitexin, and ferulic acid. This study aimed to investigate the protective effect of the ten-component combination derived from NDS (TCNDS) on ischemic stroke rats with a middle cerebral artery occlusion (MCAO) model by integrating an NMR-based metabonomics approach with biochemical assessment. Our results showed that TCNDS could improve neurobehavioral function, decrease the cerebral infarct area, and ameliorate pathological features in MCAO model rats. In addition, TCNDS was found to decrease plasma lactate dehydrogenase (LDH) and malondialdehyde (MDA) production and increase plasma superoxide dismutase (SOD) production. Furthermore,

Topics: Animals; Apigenin; Brain; Brain Ischemia; Drugs, Chinese Herbal; Ginsenosides; Infarction, Middle Cerebral Artery; Isoflavones; L-Lactate Dehydrogenase; Magnetic Resonance Spectroscopy; Male; Malondialdehyde; Metabolomics; Oxidative Stress; Rats; Rats, Wistar; Stroke; Superoxide Dismutase

Notoginsenoside R1 (NGR1) is a novel phytoestrogen that is isolated from Panax notoginseng. We have recently found that NGR1 showed neuroprotection in vitro against oxidative stress through estrogen receptor (ER)-dependent activation of Akt/Nrf2 pathways. However, whether NGR1 has neuroprotective effect against cerebral ischemia-reperfusion (I/R) injury in vivo is unknown. In this study, we used in vivo and in vitro models of cerebral I/R injury that demonstrate middle cerebral artery occlusion and reperfusion in rats, as well as oxygen-glucose deprivation followed by reoxygenation (OGD/R) in primary cortical neurons. These models were used to evaluate NGR1 neuroprotection. Three-day pretreatment with NGR1 (20 mg/kg; i.p.) significantly improved neurologic outcomes and reduced cerebral infarct volume. Pretreatment of primary cortical neurons with NGR1 (25 μM) for 24 h prevented apoptosis and oxidative stress induced by OGD/R. NGR1 inhibited apoptosis by inhibiting mitochondrial membrane potential disruption, caspase-3 activation, and DNA fragmentation. NGR1 prevented oxidative stress by suppressing NADPH oxidase- and mitochondrion-derived superoxide and inhibiting production of malondialdehyde, protein carbonyl, and 8-hydroxydeoxyguanosine in vivo and in vitro. NGR1 induced ER-dependent activation of Akt/Nrf2 pathways by increasing ERα, ERβ, phospho-Akt, phospho-GSK3β, nuclear Nrf2, and HO-1 expression in vivo and in vitro. Pretreatment with ICI-182780, LY294002, or Snpp abolished NGR1-mediated neuroprotection against oxidative stress and apoptosis in vitro. In conclusion, NGR1 showed neuroprotection against cerebral I/R injury in vivo and in vitro. The mechanism of NGR1 neuroprotection involves inhibition of NADPH oxidase activity and mitochondrial dysfunction via ER-dependent activation of Akt/Nrf2 pathways.

Topics: Animals; Brain Ischemia; Ginsenosides; Infarction, Middle Cerebral Artery; Male; Mitochondria; Molecular Structure; NADPH Oxidases; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Reperfusion Injury; Superoxides