Tian Shung Wu

Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats.

We examined the neuroprotective action of a standardized extract of Ginkgo biloba leaves (EGb 761) in permanent and transient middle cerebral artery (MCA) occlusion models in Sprague‐Dawley rats. Forty‐four animals were given either EGb 761 (50–200 mg/kg) or vehicle intraperitoneally, 1 hr before permanent MCA occlusion, to evaluate the dose‐response effects. An additional 58 animals received EGb 761 (200 mg/kg) or vehicle, 0.5– 4 hr after permanent MCA occlusion, for establishing the therapeutic window. Delayed treatment was also employed in 110 animals treated with either EGb 761 (100–200 mg/kg) or vehicle at 2–3 hr following transient focal cerebral ischemia induced by MCA occlusion for 2 hr. Neurobehavioral scores were determined 22–24 hr after permanent MCA occlusion and either 3 or 7 days after transient MCA occlusion, and brain infarction volumes were measured upon sacrifice. Local cortical blood flow (LCBF) was serially measured in a subset of animals receiving EGb 761 (100–200 mg/kg) or vehicle, 0.5 hr and 2 hr after permanent and transient MCA occlusion, respectively. Relative to vehicle‐treated controls, rats pretreated with EGb761 (100 and 200 mg/kg) had significantly reduced infarct volumes, by 36% and 49%, respectively, and improved sensory behavior (P < 0.05). Delayed treatment with EGb 761 also significantly reduced brain infarction, by 20–29% and 31%, when given up to 2 and 3 hr following transient and permanent MCA occlusion, respectively, whereas improved neurobehavioral scores were noted up to 2 hr after the onset of MCA occlusion (P < 0.05). LCBF was significantly improved in the ipsilateral cortex following the EGb 761 treatment, whereas a higher dose showed a more sustained effect. In conclusion, EGb 761 protected against transient and permanent focal cerebral ischemia and was effective after a prolonged reperfusion period even when therapy is delayed up to 2 hr. This neuroprotection may be at least partially attributed to the beneficial effects of selectively improved LCBF in the area at risk of infarction.

Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia

Abstract:  We have previously shown that melatonin reduces infarct volumes and enhances neurobehavioral and electrophysiological recoveries following transient middle cerebral artery (MCA) occlusion in rats. In the study, we examined whether melatonin would display neuroprotection against neuronal, axonal and oligodendrocyte pathology after 24 hr of reperfusion following 1 hr of MCA occlusion in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the commencement of reperfusion. Neurological deficits were assessed 24 hr after ischemia. Gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protein and microtubule‐associated protein tau‐1 immunohistochemistry to identify postischemic disrupted axonal flow and oligodendrocyte pathology, respectively. Oxidative damage was assessed by 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) and 4‐hydroxynonenal (4‐HNE) immunohistochemistry. Relative to controls, melatonin‐treated animals not only had a significantly reduced volume of gray matter infarction by 42% (P < 0.001), but also exhibited a decreased score of axonal damage by 42% (P < 0.001) and a reduction in the volume of oligodendrocyte pathology by 58% (P < 0.005). Melatonin‐treated animals also had significantly reduced immunopositive reactions for 8‐OHdG and 4‐HNE by 53% (P < 0.001) and 49% (P < 0.001), respectively. In addition, melatonin improved sensory and motor neurobehavioral outcomes by 47 and 30%, respectively (P < 0.01). Thus, delayed (1 hr) treatment with melatonin reduced both gray and white matter damage and improved neurobehavioral outcomes following transient focal cerebral ischemia in mice. The finding of reduced oxidative damage observed with melatonin suggests that its major mechanisms of action are mediated through its antioxidant and radical scavenging activity.

Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats

Abstract:  We have previously shown that exogenous melatonin improves the preservation of the blood–brain barrier (BBB) and neurovascular unit following cerebral ischemia–reperfusion. Recent evidence indicates that postischemic microglial activation exaggerates the damage to the BBB. Herein, we explored whether melatonin mitigates the cellular inflammatory response after transient focal cerebral ischemia for 90 min in rats. Melatonin (5 mg/kg) or vehicle was given intravenously at reperfusion onset. Immunohistochemistry and flow cytometric analysis were used to evaluate the cellular inflammatory response at 48 hr after reperfusion. Relative to controls, melatonin‐treated animals did not have significantly changed systemic cellular inflammatory responses in the bloodstream (P > 0.05). Melatonin, however, significantly decreased the cellular inflammatory response by 41% (P < 0.001) in the ischemic hemisphere. Specifically, melatonin effectively decreased the extent of neutrophil emigration (Ly6G‐positive/CD45‐positive) and macrophage/activated microglial infiltration (CD11b‐positive/CD45‐positive) by 51% (P < 0.01) and 66% (P < 0.01), respectively, but did not significantly alter the population composition of T lymphocyte (CD3‐positive/CD45‐positive; P > 0.05). This melatonin‐mediated decrease in the cellular inflammatory response was accompanied by both reduced brain infarction and improved neurobehavioral outcome by 43% (P < 0.001) and 50% (P < 0.001), respectively. Thus, intravenous administration of melatonin upon reperfusion effectively decreased the emigration of circulatory neutrophils and macrophages/monocytes into the injured brain and inhibited focal microglial activation following cerebral ischemia–reperfusion. The finding demonstrates melatonins inhibitory ability against the cellular inflammatory response after cerebral ischemia–reperfusion, and further supports its pleuripotent neuroprotective actions suited either as a monotherapy or an add‐on to the thrombolytic therapy for ischemic stroke patients.

New constituents and antiplatelet aggregation and anti-HIV principles of Artemisia capillaris

Five new constituents including a flavonoid, artemisidin A (1), and four coumarins, artemicapins A (2), B (3), C (4) and D (5), together with 70 known compounds (6-75), have been isolated and characterized from the aerial part of Artemisia capillaris. The structures of these compounds were determined from spectral analyses and/or chemical evidence. Among them, 15 compounds (3, 6, 10, 18. 30-32, 38-41, 44, 45, 51, and 55) showed antiplatelet aggregation activity and three compounds (10, 17, and 51) demonstrated significant activity against HIV replication in H9 lymphocytic cells.

Alkaloids and other constituents from Tribulus terrestris

Three new compounds, terrestribisamide, 25R-spirost-4-en-3,12-dione and tribulusterine, together with 10 known compounds, N-p-coumaroyltyramine, terrestriamide, hecogenin, aurantiamide acetate, xanthosine, fatty acid ester, ferulic acid, vanillin, p-hydroxybenzoic acid and β-sitosterol, were isolated and characterized from dried fruits of Tribulus terrestris. Structures of these compounds were determined by spectral analysis.

MELATONIN DECREASES NEUROVASCULAR OXIDATIVE/NITROSATIVE DAMAGE AND PROTECTS AGAINST EARLY INCREASES IN THE BLOOD–BRAIN BARRIER PERMEABILITY AFTER TRANSIENT FOCAL CEREBRAL ISCHEMIA IN MICE

Abstract:  We have recently shown that melatonin decreases the late (24 hr) increase in blood–brain barrier (BBB) permeability and the risk of tissue plasminogen activator‐induced hemorrhagic transformation following ischemic stroke in mice. In the study, we further explored whether melatonin would reduce postischemic neurovascular oxidative/nitrosative damage and, therefore, improve preservation of the early increase in the BBB permeability at 4 hr after transient focal cerebral ischemia for 60 min in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the beginning of reperfusion. Hydroethidine (HEt) in situ detection and immunohistochemistry for nitrotyrosine were used to evaluate postischemic accumulation in reactive oxygen and nitrogen species, respectively, in the ischemic neurovascular unit. BBB permeability was evaluated by spectrophotometric and microscopic quantitation of Evans Blue leakage. Relative to controls, melatonin‐treated animals not only had a significantly reduced superoxide accumulation in neurovascular units in boundary zones of infarction, by reducing 35% and 54% cytosolic oxidized HEt in intensity and cell‐expressing percentage, respectively (P < 0.001), but also exhibited a reduction in nitrotyrosine by 52% (P < 0.01). Additionally, melatonin‐treated animals had significantly reduced early postischemic disruption in the BBB permeability by 53% (P < 0.001). Thus, melatonin reduced postischemic oxidative/nitrosative damage to the ischemic neurovascular units and improved the preservation of BBB permeability at an early phase following transient focal cerebral ischemia in mice. The findings further highlight the ability of melatonin in anatomical and functional preservation for the ischemic neurovascular units and its relevant potential in the treatment of ischemic stroke.

Carbazole alkaloids from Clausena excavata and their biological activity

Five new carbazole alkaloids, clausines B, E, H, I and K, as well as 22 known compounds, were isolated from the stem bark of Clausena excavata. The structures were established from spectral data and chemical transformation. These compounds showed significant inhibition of rabbit platelet aggregation and caused vasocontraction. The crude methanol extract, partitioned layers and chromatographic fractions revealed the presence of promotive and inhibitive constituents, simultaneously. These results might explain the philosophy of use in Chinese medicine, in that the dose and content variation in a prescription produced different, promotive or inhibitive, effects on therapy.

Alkaloidal and other constituents from the root bark of Clausena excavata

Ten new carbazole alkaloids, clausine-M, -N, -O, -P, -Q, -R, -S, -U, -V and clausenatine-A, together with 39 known compounds were isolated and identified from the acetone extract of the root bark of Clausena excavata. Their structures have been elucidated by spectroscopic analyses. This is the first report of a decarboxylated carbazole alkaloid from a natural source. The presence of a C23-skeleton carbazole alkaloid in a plant of Clausena genus is also reported for the first time.

Monoterpene glycosides from Paeonia suffruticosa

Abstract Six new monoterpene glycosides, namely mudanpioside-A to -F, were isolated as minor components from and ethanol extract of the root cortex of Paeonia suffruticosa . Their structures have been established on the basis of spectral evidence. In addition, five known glycosides, paeoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, benzoyloxypaeoniflorin and apiopaeonoside, were also isolated and characterized.

Phenolic Constituents from the Stem Bark of Magnolia officinalis

Three new compounds, magnolianone (1), erythro-honokitriol (2), and threo-honokitriol (3), together with 14 known compounds, magnaldehyde (4), magnatriol B (5), randaiol (6), obovatol (7), magnolignan B (8a and 8b), magnolol, honokiol (9), p-hydroxylbenzaldehyde, coniferaldehyde, coniferol alcohol, syringaldehyde, syringaresinol, and acteoside, were isolated from the MeOH-soluble part of a water extract of the stem bark of Magnolia officinalis. Among these compounds, 2-8b were studied for anti-inflammatory and antioxidative activities. Compound 7 displayed more potent antioxidative potential than 9. Compounds 4-7 effectively inhibited LPS-induced NO production, whereas 5 and 6 were more potent than 9.