Discovering the Effects of Fisetin on NF-κB/NLRP-3/NRF-2 Molecular Pathways in a Mouse Model of Vascular Dementia Induced by Repeated Bilateral Carotid Occlusion

Abstract

Vascular dementia (VaD) is the second leading cause of dementia. The majority of VaD patients have cognitive abnormalities, which are caused by cerebral hypoperfusion-induced ischemia, endothelial dysfunction, oxidative stress, and neuroinflammation. Natural products are receiving increasing attention for the treatment of neuroinflammatory diseases. The aim of this study was to investigate the molecular pathways underlying the protective effects of fisetin, a flavonoid present in many fruits and vegetables, in a mouse model of VaD induced by repeated ischemia-reperfusion (IR) of the total bilateral carotid artery. Here, we found that VaD caused brain injury, lipid peroxidation, and neuronal death in the hippocampus, as well as astrocyte and microglial activation, and reduced BDNF neurotrophic factor expression together with behavioral alterations. In addition, VaD induced the activation of inflammasome components (NLRP-3, ASC, and caspase 1), and their downstream products (IL-1β and IL-18) release and promote activation of apoptotic cell death. Fisetin attenuated histological injury, malondialdehyde levels, inflammasome pathway activation, apoptosis, as well as increased BDNF expression, reduced astrocyte, microglial activation, and cognitive deficits. In conclusion, the protective effects of fisetin could be due to the inhibition of the ROS-induced activation of NF-κB/NLRP3 inflammasome together with the activation of antioxidant Nrf2/HO-1, suggesting a possible crosstalk between these molecular pathways.

The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress

“…Fisetin, chemically 3,7,3′,4′-tetrahydroxyflavone or 7,3′,4′-flavon-3-ol is a polyhydroxy flavonoid with various pharmacological potentials like antioxidant ( Khan et al, 2013 ), anti-inflammatory ( Wu et al, 2022 ), anti-cancer ( Lin et al, 2016 ), neuroprotective ( Kumar et al, 2020 ) and is used in vascular dementia ( Cordaro et al, 2022 ). It occurs in numerous fruits and vegetables, such as grapes, apples, onions, strawberries, and cucumbers ( Cordaro et al, 2022 ). It is found in the range of 2–160 μg/g in different food plants, and the average daily intake of this flavonol in humans has estimated about 0.4 mg ( Cordaro et al, 2022 ).…”

“…It occurs in numerous fruits and vegetables, such as grapes, apples, onions, strawberries, and cucumbers ( Cordaro et al, 2022 ). It is found in the range of 2–160 μg/g in different food plants, and the average daily intake of this flavonol in humans has estimated about 0.4 mg ( Cordaro et al, 2022 ). Because of its various bioactive properties, fisetin is considered a health-promoting factor agent and some dietary supplements containing fisetin have been marketed ( Grynkiewicz and Demchuk, 2019 ).…”

Açai Berry Mitigates Vascular Dementia-Induced Neuropathological Alterations Modulating Nrf-2/Beclin1 Pathways

“…Mice were subjected to temporary bilateral carotid occlusion as previously described by Cordaro et al [ 40 ]. Briefly, following anesthesia, the bilateral carotid arteries underwent three cycles of ligation and release lasting a total of 10 min each.…”

“…After the threading was taken out, the incision was stitched up. After 15 days of induction, the mice were sacrificed, and their brains were removed and processed for histological and biochemical analysis [ 40 , 41 ].…”

“…Brains were stained with hematoxylin/eosin (H/E) or cresyl-violet and blindly analyzed using light microscopy LeicaDM6 connected to an imaging system (LasX Navigator)(Leica Microsystem, Buccinasco, Italy) by two investigators without knowledge of the experimental groups [ 46 , 47 , 48 ]. The severity of brain injury and numbers of dead cells was assessed as previously described [ 40 , 41 ].…”