Abstract
BackgroundRecent studies have demonstrated an inflammatory response associated with the pathophysiology of cerebral ischemia. The beneficial effects of anti-inflammatory drugs in cerebral ischemia have been documented. When screening natural compounds for drug candidates in this category, we isolated 6-O-acetyl shanzhiside methyl ester (ND02), an iridoid glucoside compound, from the leaves of Lamiophlomis rotata (Benth.) Kudo. The objectives of this study were to determine the effects of ND02 on a cultured neuronal cell line, SH-SY5Y, in vitro, and on experimental ischemic stroke in vivo.MethodsFor TNF-α-stimulated SH-SY5Y cell line experiments in vitro, SH-SY5Y cells were pre-incubated with ND02 (20 μM or 40 μM) for 30 min and then incubated with TNF-α (20 ng/ml) for 15 min. For in vivo experiments, rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h followed by reperfusion for 23 h.ResultsND02 treatment of SH-SY5Y cell lines blocked TNF-α-induced nuclear factor-κB (NF-κB) and IκB-α phosphorylation and increased Akt phosphorylation. LY294002 blocked TNF-α-induced phosphorylation of Akt and reduced the phosphorylation of both IκB-α and NF-κB. At doses higher than 10 mg/kg, ND02 had a significant neuroprotective effect in rats with cerebral ischemia and reperfusion (I/R). ND02 (25 mg/kg) demonstrated significant neuroprotective activity even after delayed administration 1 h, 3 h and 5 h after I/R. ND02, 25 mg/kg, attenuated histopathological damage, decreased cerebral Evans blue extravasation, inhibited NF-κB activation, and enhanced Akt phosphorylation.ConclusionThese data show that ND02 protects brain against I/R injury with a favorable therapeutic time-window by alleviating cerebral I/R injury and attenuating blood-brain barrier (BBB) breakdown, and that these protective effects may be due to blocking of neuronal inflammatory cascades through an Akt-dependent NF-κB signaling pathway.
Highlights
Recent studies have demonstrated an inflammatory response associated with the pathophysiology of cerebral ischemia
There is ample evidence indicating that nuclear factor-B (NF-B) is activated in cerebral ischemia and reperfusion (I/R), especially in neurons [5,6,7,8]
Previous studies have shown that aspirin and several structurally diverse compounds provide neuroprotection during cerebral ischemia via inhibition of NF-B activation [9,10,11,12,13]
Summary
Recent studies have demonstrated an inflammatory response associated with the pathophysiology of cerebral ischemia. The beneficial effects of anti-inflammatory drugs in cerebral ischemia have been documented. The inflammatory response to brain injury plays a vital role in the pathogenesis of. There is ample evidence indicating that NF-B is activated in cerebral ischemia and reperfusion (I/R), especially in neurons [5,6,7,8]. This suggests that inhibition of NF-B may represent a treatment strategy in ischemic stroke. Akt signaling exerts its neuroprotective role in cerebral ischemia animal models [18,19,20] via blocking of NF-B activation, through IkB phosphorylation and degradation [21]
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