Effects of fisetin on hyperhomocysteinemia-induced experimental endothelial dysfunction and vascular dementia

Abstract

This study was designed to investigate the effects of fisetin (FST) on hyperhomocysteinemia (HHcy)-induced experimental endothelial dysfunction (ED) and vascular dementia (VaD) in rats. Wistar rats were randomly divided into 8 groups: control, vehicle control, l-methionine, FST (5, 10, and 25 mg/kg, p.o.), FST-per se (25 mg/kg, p.o.), and donepezil (0.1 mg/kg, p.o.). l-Methionine administration (1.7 g/kg, p.o.) for 32 days induced HHcy. ED and VaD induced by HHcy were determined by vascular reactivity measurements, behavioral analysis using Morris water maze and Y-maze, along with a biochemical and histological evaluation of thoracic aorta and brain tissues. Administration of l-methionine developed behavioral deficits; triggered brain lipid peroxidation (LPO); compromised brain acetylcholinesterase activity (AChE); and reduced the levels of brain superoxide dismutase (SOD), brain catalase (CAT), brain reduced glutathione (GSH), and serum nitrite; and increased serum homocysteine and cholesterol levels. These effects were accompanied by decreased vascular NO bioavailability, marked intimal thickening of the aorta, and multiple necrotic foci in brain cortex. HHcy-induced alterations in the activities of SOD, CAT, GSH, AChE, LPO, behavioral deficits, ED, and histological aberrations were significantly attenuated by treatment with fisetin in a dose-dependent manner. Collectively, our results indicate that fisetin exerts endothelial and neuroprotective effects against HHcy-induced ED and VaD.

Trefoil Factor 3, Cholinesterase and Homocysteine: Potential Predictors for Parkinson’s Disease Dementia and Vascular Parkinsonism Dementia in Advanced Stage

“…These higher levels of Hcy in PDD/VPD patients may damage neuron and vascular endothelial cells in the brain, inducing neuroinflammation [ 23 , 65 , 66 ]. High levels of Hcy could break down the blood brain barrier (BBB) and lead to cerebrovascular dysfunction, which subsequently modulates the activities of enzymes and neuropeptides and influences hippocampal volume in the pathophysiological processes of dementia [ 67 - 69 ]. It has been shown that Hcy could stimulate superoxide and hydrogen peroxide generation in vivo and in vitro [ 70 ] and that ChEs activities are inhibited by high level of Hcy mediated by the generation of free radical formation [ 71 - 73 ].…”

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

“…The highest concentration of fisetin was found in strawberries followed by apple and persimmon [ 18 ]. Fisetin has been the topic of research in current years due to its anticancer, anti-inflammatory, memory-enhancing, and neuroprotective properties [ 19 ]. Fisetin has also been discovered to have substantial antioxidant capabilities in membrane settings, and it has been proposed as a possible treatment agent for a variety of free radical-mediated disorders [ 20 ].…”

“…Fisetin has also been discovered to have substantial antioxidant capabilities in membrane settings, and it has been proposed as a possible treatment agent for a variety of free radical-mediated disorders [ 20 ]. Previous studies also showed the neuroprotective effects of Fisetin in experimental models of dementia induced by hyperhomocysteinemia [ 19 ] as well as of occlusion of the middle cerebral artery (MCAO) [ 21 ]. It was well known that the antioxidant effects of fisetin could be attributable to the activation of Nrf2/HO-1 [ 22 ].…”

Fisetin Prevents Acetaminophen-Induced Liver Injury by Promoting Autophagy

“…It has been reported that FST inhibits inflammation related cytokines like TNF-a, IL-6, and NF-kB in streptozotocin (STZ)-induced diabetic cardiomyopathy rats (Althunibat et al, 2019). FST has also been shown to upregulate glutathione (GSH) in isoproterenol-induced cardiac ischemic injury rats and hyperhomocysteinemia-induced endothelial dysfunction rats (Hemanth Kumar et al, 2017;Garg et al, 2019). Thanks to its chemical structure ( Figure 1A), FST has an electron donating capacity to scavenge free radicals, which could have implications for diseases caused by oxidative stress (Khan et al, 2013).…”