Oxidative
stress plays a vital role in the development of cerebral
ischemic/reperfusion (I/R). Targeting oxidative stress is proposed
to be an effective strategy to treat cerebral I/R injury. Gentiana macrophylla Pall is reported to have a potential
protective effect against stroke. Swertiamarin (Swe), an active secoiridoid
glycoside compound isolated from Gentiana macrophylla Pall, has been reported to possess antioxidative potential. This
study is to explore whether Swe could prevent brain from I/R injury,
and the related mechanisms of oxidative stress are also elucidated
using mice middle cerebral artery occlusion (MCAO) model and primary
hippocampal neurons oxygen-glucose deprivation/reperfusion (OGD/R)
model. Swe (25, 100, or 400 mg/kg) was pretreated intraperitoneally
for 7 days until establishment of the MCAO model, while hippocampal
neurons were maintained in Swe (0.1, 1, or 10 μM) in the entire
process of reoxygenation. The results indicated that Swe pretreatment
markedly decreased infarct volume, apoptotic neurons, and oxidative
damage and promoted neurologic recovery in vivo. It also decreased
reactive oxygen species (ROS) and increased cell viability in vitro.
Western blot analyses and immunofluorescence staining demonstrated
that Swe pretreatment promoted Nrf2 nuclear translocation from Keap1-Nrf2
complex and enhanced the expressions of NAD(P)H: quinone oxidoreductase-1
(NQO1) and heme oxygenase-1 (HO-1) both in vivo and in vitro, while
the expressions could be reversed by a Nrf2 inhibitor. The binding
mode of Keap1 with Swe was also proposed by covalent molecular docking.
Collectively, Swe could be considered as a promising protective agent
against cerebral I/R injury through suppressing oxidative stress by
activation of the Nrf2 protective pathway.
Oxymatrine (OMT), a quinolizidine alkaloid extracted from traditional Chinese herb Sophora flavescens Ait, has drawn attention because of its beneficial bioactivities against hypoxic–ischemic brain damage (HIBD). However, the underlying molecular mechanism remains unclear. In this study, we determined the in vivo and in vitro effects of OMT on seven-day old Sprague–Dawley rats with HIBD and in a rat model of primary hippocampal neuron oxygen glucose deprivation reoxygenation (OGD/R). This study was aimed to evaluate whether OMT exerted neuroprotective effects mediated by the (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) PI3K/Akt/mTOR pathway after HIBD. Experimental results showed that the alkaloid significantly improved the early neurofunctional development, brain water content, abnormal pathological changes, and necrosis of neurons after HIBD. Moreover, OMT enhanced the cell viability and stabilized the mitochondrial permeability transition pore in the primary hippocampal neurons after OGD/R. OMT significantly decreased the autophagosome generation, elevated the expression of PI3K, Akt, and mTOR, and simultaneously reversed the mRNA expression of microtubule-associated protein 1-light chain 3 (LC3), Beclin-1, and sequestosomel (P62) induced by hypoxia and ischemia. However, these protective effects against HIBD could be suppressed when rapamycin, a specific inhibitor of mTOR, was included. Hence, the OMT exerted neuroprotective effects against HIBD by attenuating excessive autophagy by mediating the PI3K/Akt/mTOR pathway.
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