NEUROPROTECTIVE EFFECT OF CAJANINSTILBENE ACID AGAINST CEREBRAL ISCHEMIA
AND REPERFUSION DAMAGES BY ACTIVATING AMPK/NRF2 PATHWAY
BACKGROUND AND PURPOSE Neuroprotection is an important strategy for
ischemic stroke treatment. Cajaninstilbene acid (CSA), a unique
stilbenoid with a styryl group, is a potential neuroprotective agent.
Hence, this study aimed to evaluate the neuroprotective effect and
molecular mechanism of CSA against cerebral ischemia/reperfusion (I/R)
damages. EXPERIMENTAL APPROACH The ischemic stroke was modeled by oxygen
and glucose deprivation/reoxygenation (OGD/R) in SH-SY5Y cells and
transient middle cerebral artery occlusion/reperfusion (MCAO/R) in rats.
Tert-butyl hydroperoxide (t-BHP) was used to induce oxidative stress in
cells. The signaling pathways were analyzed by Western blotting and
inhibitor blocking. KEY RESULTS CSA possessed significant
neuroprotective activity, as evidenced by the reduced cell death in
OGD/R or t-BHP injured cells, and decreased infarct volume and
neurological deficits in MCAO/R rats. Further studies indicated that the
protective effect was achieved via the antioxidant activity of CSA,
which decreased the oxidative stress and its related mitochondrial
dysfunction in cells. Notably, Nrf2 was activated in cells and MCAO/R
rats by CSA, and the inhibition of Nrf2 by brusatol weakened
CSA-mediated neuroprotection. Furthermore, after applying a series of
kinase inhibitors, CSA-induced Nrf2 activation was markedly inhibited by
BML-275 (an AMPK inhibitor), implying that AMPK was the dominant kinase
to regulate the Nrf2 pathway for CSA’s neuroprotective effects with
enhanced AMPK phosphorylation observed both in vivo and in vitro.
CONCLUSION AND IMPLICATION CSA exerted neuroprotection via activating
AMPK/Nrf2 pathway to reduce I/R-induced cellular oxidative stress and
mitochondrial disfunction. CSA could be a potential neuroprotective drug
candidate for the treatment of ischemic stroke.