Quercetin-SPIONs enhance neuroprotection in aged rat tMCAO model via modulation of GABA B receptor and CHOP mRNA expression

Abstract

GABAB receptors are key regulators of neuronal excitability via slow inhibitory mechanisms. Their downregulation in cerebral ischemic stroke impairs excitotoxicity and neuronal death. Quercetin (QC), a well-known flavonoid, has neuroprotective properties but is limited by poor bioavailability and low water solubility. To overcome these restrictions, quercetin was conjugated with superparamagnetic iron oxide nanoparticles (QCSPIONs) and their effectiveness as a treatment was evaluated in an aged rat model of transient middle cerebral artery occlusion (tMCAO). Animals were given QC, QCSPIONs, and vehicle orally for 14 days after reperfusion following exposure to tMCAO. Neurological deficits, infarct volume, brain edema, sensory-motor function, learning, memory, and hippocampal mRNA expression of GABAB receptor subunits, CHOP, Bax, and Bcl-2 were evaluated. Both QC and QCSPIONs significantly enhanced neurological function, reduced infarct volume, alleviated brain edema, and improved cognitive recovery. QCSPIONs showed higher efficacy in comparison to free QC, as evidenced by better performance in behavioral tests, and greater modulation of gene expression. Treatment with QC and QCSPIONs reduced CHOP and the Bax/Bcl-2 ratio while increasing the mRNA expression of GABAB receptor subunits and Bcl-2, suggesting anti-apoptotic and neuroprotective properties. These findings propose that QCSPIONs increase neuroprotection against excitotoxicity by modulating GABAB receptor and CHOP mRNA expression in aged rats following ischemic stroke. Our study highlights the therapeutic potential of QCSPIONs as a novel strategy for moderating brain injury and improving functional recovery after cerebral ischemia/reperfusion. © 2025 Elsevier B.V.