Abstract
Context: Hesperidin (HSP), a flavanoglycone found in citrus fruits, has antioxidant, anti-inflammatory and neuroprotective properties.Objective: This study evaluates the protective effect of HSP on l-methionine-induced hyperhomocysteinemia (HHcy) in rats.Materials and methods: Male Wistar rats were randomly divided into seven groups as DMSO, l-methionine, HSP (25, 50 and 100 mg/kg), HSP-per se (100 mg/kg) and donepezil (0.1 mg/kg). HHcy was induced by oral administration of l-methionine (1.7 g/kg) for 32 days. From the 14th day of study HSP (25, 50 and 100 mg/kg) and donepezil was administered orally to l-methionine-treated rats. Cognitive impairment induced by HHcy was determined using the Morris water maze (MWM) and Y-maze on video tracking system (28th–32nd day). Different biomarkers of HHcy in serum and brain and vascular reactivity were evaluated and histopathology (thoracic aorta and brain) was done.Results: HSP (100 mg/kg) treatment in l-methionine-treated rats exhibited significant (p < 0.001) dose-dependent activity and reduced behavioural deficits, brain acetylcholinesterase (25.99 ± 2.36 versus 10.73 ± 1.26 μmoles/mg), brain lipid peroxidation (15.25 ± 1.65 versus 6.18 ± 0.74 nM/mg), serum homocysteine (Hcy) (22.37 ± 0.30 versus 11.01 ± 1.01 μg/mL) and serum cholesterol (182.7 ± 2.15 versus 101.5 ± 2.76 mg/dL) and increased brain antioxidant levels. HSP significantly (p < 0.001) reduced endothelial dysfunction (ED) by abolishing the effect of l-methionine on acetylcholine-induced endothelial-dependent relaxation and increased serum nitrite and vascular nitric oxide bioavailability along with the restoration of histological aberrations.Conclusion: HSP exerts a protective effect on HHcy by abrogating oxidative stress, ED and neurotoxicity.
Highlights
Vascular dementia (VaD) is a disorder of cognitive impairment along with dysfunction of the vascular endothelium
dimethyl sulphoxide (DMSO)-treated animals have shown a downward trend in their escape latency time (ELT) and there was a significant fall in the day 4 ELT when compared to day 1 ELT of these rats (p < 0.001), reflecting normal learning ability
Further administration of HSP (50 and 100 mg/kg) and donepezil there is a significant prevention of rise in the day 4 ELT (p < 0.001) and decrease in the day 5 time spent in all three quadrants (TSTQ) in a significant manner (p < 0.001) indicating a reversal of L-methionine-induced impairment of memory (Table 1). p < 0.01 indicates comparison of HSP100 mg/kg with HSP-50 mg/kg
Summary
Vascular dementia (VaD) is a disorder of cognitive impairment along with dysfunction of the vascular endothelium. Oxidative stress has been implicated as an important risk factor in the neuropathology of several neurodegenerative disorders characterized by cognitive deficits (Coyle & Puttfarcken 1993; Olanow 1993). Literature survey shows a positive, dose-dependent relationship between mild to moderate increase in plasma total Hcy concentrations and the risk of neurodegenerative diseases, such as VaD, cognitive impairment or stroke (Herrmann & Obeid 2011). Several studies reported that HHcy inhibits the expression of antioxidant enzymes and produces complex changes in blood vessels that include ED, oxidative stress, pro-inflammatory effects such as expression of tumour necrosis factor and inducible nitric oxide (NO) synthase (Heinecke 1988; Hankey & Eikelboom 1999; Lentz et al 2000)
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