Inflammatory response contributes to
brain injury after
ischemia and reperfusion (I/R). Our previous literature has shown
isoquercetin plays an important role in protecting against cerebral I/R injury. The present study was conducted to further investigate the effect of
isoquercetin on
inflammation-induced neuronal injury in I/R rats with the involvement of cyclic
adenosine monophosphate (
cAMP)/protein kinase A (PKA) and inhibitor of NF-κB (I-κB)/
nuclear factor-kappa B (NF-κB) signaling pathway mediated by
Toll-like receptor 4 (TLR4) and
C5a receptor 1 (C5aR1). In vivo
middle cerebral artery occlusion and reperfusion (MCAO/R) rat model and in vitro
oxygen-
glucose deprivation and reperfusion (OGD/R) neuron model were used. MCAO/R induced neurological deficits, cell apoptosis, and release of
cytokines such as
tumor necrosis factor (TNF)-α,
interleukin (IL)-1β, and
IL-6 in ischemic brain in rats. Simultaneously, the expression of TLR4 and C5aR1 was significantly up-regulated in both MCAO/R rats and OGD/R neurons, accompanied with the inhibition of cAMP/PKA signaling and activation of I-κB/NF-κB signaling in the cortex of MCAO/R rats. Over-expression of C5aR1 in neurons induced decrease of cell viability, exerting similar effects with OGD/R injury.
Isoquercetin acted as a
neuroprotective agent against I/R
brain injury to suppress inflammatory response and improve cell recovery by inhibiting TLR4 and C5aR1 expression, promoting cAMP/PKA activation, and inhibiting I-κB/NF-κB activation and
Caspase 3 expression. TLR4 and C5aR1 contributed to
inflammation and apoptosis via activating cAMP/PKA/I-κB/NF-κB signaling during cerebral I/R, suggesting that this signaling pathway may be a potent therapeutic target in
ischemic stroke.
Isoquercetin was identified as a
neuroprotective agent, which maybe a promising therapeutic agent used for the treatment of
ischemic stroke and related diseases.