Isoquercetin Improves Inflammatory Response in Rats Following Ischemic Stroke

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Background:

• Inflammatory responses exacerbate brain injury following ischemia and reperfusion (I/R).
• Previous studies indicate isoquercetin possesses protective effects against cerebral I/R injury.
• The interplay between Toll-like receptor 4 (TLR4), C5a receptor 1 (C5aR1), and inflammatory signaling in I/R injury requires further elucidation.

Purpose of the Study:

• To investigate the neuroprotective effects of isoquercetin on inflammation-induced neuronal injury in an ischemic stroke model.
• To elucidate the role of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and inhibitor of NF-κB (I-κB)/nuclear factor-kappa B (NF-κB) signaling pathways, mediated by TLR4 and C5aR1, in I/R-induced brain injury.
• To assess isoquercetin's potential as a therapeutic agent for ischemic stroke.

Main Methods:

• Establishment of in vivo middle cerebral artery occlusion and reperfusion (MCAO/R) rat models and in vitro oxygen-glucose deprivation and reperfusion (OGD/R) neuron models.
• Assessment of neurological deficits, cell apoptosis, cytokine release (TNF-α, IL-1β, IL-6), and expression of TLR4, C5aR1, cAMP/PKA, and I-κB/NF-κB signaling components.
• Evaluation of isoquercetin's effects on these parameters in MCAO/R rats and OGD/R neurons.

Main Results:

• MCAO/R induced significant neurological deficits, apoptosis, and pro-inflammatory cytokine release in rats.
• TLR4 and C5aR1 expression were upregulated in both MCAO/R rats and OGD/R neurons, correlating with inhibited cAMP/PKA and activated I-κB/NF-κB signaling.
• Isoquercetin administration suppressed inflammation, reduced apoptosis, inhibited TLR4 and C5aR1 expression, promoted cAMP/PKA activity, and attenuated I-κB/NF-κB activation and Caspase 3 expression.

Conclusions:

• TLR4 and C5aR1 mediate inflammation and apoptosis in cerebral I/R injury through the cAMP/PKA/I-κB/NF-κB signaling pathway.
• This pathway represents a potential therapeutic target for ischemic stroke.
• Isoquercetin demonstrates significant neuroprotective properties and may serve as a promising therapeutic agent for ischemic stroke and related conditions.