Quercetin Alleviated Inflammasome-Mediated Pyroptosis and Modulated the mTOR/P70S6/P6/eIF4E/4EBP1 Pathway in Ischemic Stroke

Abstract

Stroke ranks as the world’s second most prevalent cause of mortality, and it represents a major public health concern with profound economic and social implications. In the present study, we elucidated the neuroprotective role of quercetin on NLRP3-associated pyroptosis, Nrf2-coupled anti-inflammatory, and mTOR-dependent downstream pathways. Male Sprague Dawley rats were subjected to 72 h of transient middle cerebral artery ischemia, followed by the administration of 10 mg/kg of quercetin. Our findings demonstrated that MCAO induced elevated ROS which were coupled to inflammasome-mediated pyroptosis and altered mTOR-related signaling proteins. We performed ELISA, immunohistochemistry, and Western blotting to unveil the underlying role of the Nrf2/HO-1 and PDK/AKT/mTOR pathways in the ischemic cortex and striatum. Our results showed that quercetin post-treatment activated the Nrf2/HO-1 cascade, reversed pyroptosis, and modulated the autophagy-related pathway PDK/AKT/mTOR/P70S6/P6/eIF4E/4EBP1. Further, quercetin enhances the sequestering effect of 14-3-3 and reversed the decrease in interaction between p-Bad and 14-3-3 and p-FKHR and 14-3-3. Our findings showed that quercetin exerts its protective benefits and rescues neuronal damage by several mechanisms, and it might be a viable neuroprotective drug for ischemic stroke therapy.

Quercetin attenuated ischemic stroke induced neurodegeneration by modulating glutamatergic and synaptic signaling pathways

“…Evidence indicates cross-talks between NFκB and Nrf2, a transcription protein that activates the endogenous inducible antioxidant proteins such as HO-1 [ 66 , 67 ]. Our study demonstrated elevated expressions of inflammatory mediators and pro-inflammatory cytokines along with cytoprotective Nrf2 and HO-1 in the ischemic brain while quercetin modulated these changes which is consistent with previous findings that suggest a strong anti-inflammatory potential of quercetin in various models of ischemic stroke [ 28 , 29 ].…”

“…We did not employ randomization or blind allotment of rats; nevertheless, we followed the criterion of keeping animals of comparable weight in the same cohort under the same test conditions. Each of the four groups of rats was randomly assigned to receive quercetin therapy or sham surgery (n = 13/group), MCAO (middle cerebral artery occlusion), Qur + MCAO (quercetin treatment in conjunction with middle cerebral artery occlusion), sham and Qur + sham [ 29 ].…”

“…The beneficial effects of these flavonoids in various injury models, including brain ischemia, have recently been evaluated in this context [ 27 ]. Previously, we demonstrated quercetin's ability to map the expression of cortical proteins in ischemic stroke [ 28 ] and its ability to inhibit pyroptosis and modulate autophagy [ 29 ]. However, quercetin's effect on NMDAR-related signaling is yet unclear.…”

Quercetin improves homocysteine-induced learning and memory impairment in rats via AMPK/mTOR

“…It has a protective effect on neurodegenerative diseases and can signi cantly improve learning, memory, and cognitive impairmen (Paula et al, 2019). According to literature reports, Que can regulate autophagy through the DK/AKT/mTOR pathway to alleviate neurological damage caused by stroke (Alattar et al, 2023). There are also studies indicating that Quercetin can prevents COV-induced hippocampal damage by enhancing the antioxidant system and preventing cell apoptosis (Sadeghi et al, 2023).…”

Novel Multi-Antioxidant Approach for Ischemic Stroke Therapy Targeting the Role of Oxidative Stress

“…Polyphenols comprise a diverse group of antioxidants, sharing a common feature of containing at least one aromatic ring with multiple hydroxyl groups [ 54 ]. Some polyphenols, such as resveratrol [ 68 ], curcumin [ 69 ], and quercetin [ 70 ], have been studied to assess their neuroprotective effects, and several mechanisms have been implicated.…”