Beneficial Effects of Donepezil on Vascular Endothelial Dysfunction-Associated Dementia Induced by L-Methionine in Rats

Abstract

Donepezil (acetyl cholinesterase inhibitor) is a mainstay of clinical intervention to contain memory deficits of Alzheimer's disease. However, its beneficial role in endothelial dysfunction-associated dementia i. e. vascular dementia still needs to be explored. The present study was designed to investigate the effect of donepezil on vascular endothelial dysfunction, and associated memory deficits in rats. Atorvastatin (3-hydroxy-4-methyl-glutaryl (HMG)-CoA inhibitor) was taken as the standard. Rats were administered L-methionine (1.7 g/kg per day, p.o., 4 weeks and 4 days i.e. chronic treatment) to produce endothelial dysfunction and dementia. Serum nitrite level was estimated as a marker of endothelial function. Morris water maze (MWM) test was employed for assessment of memory. Brain tissue thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) were estimated to assess oxidative stress. Brain acetylcholine esterase (AChE) activity and serum total cholesterol level were also estimated. L-methionine produced endothelial dysfunction as reflected by significant decrease of serum nitrite concentration. L-methionine-treated rats performed poorly on MWM indicating impairment of memory as well. These rats also showed a significant rise in brain oxidative stress, AChE activity and serum total cholesterol levels. Donepezil (0.1 mg/kg p.o.) and atorvastatin (10 mg/kg p.o.) attenuated L-methionine-induced endothelial dysfunction. This intervention reversed L-methionine-induced rise of brain oxidative stress and AChE activity. Furthermore, atorvastatin produced a reduction of L-methionine-induced rise in serum cholesterol. The beneficial effects of donepezil may be attributed to its multiple effects and this study highlights the potential of donepezil in vascular dementia.

Hesperidin, a citrus flavonoid, protects against l -methionine-induced hyperhomocysteinemia by abrogation of oxidative stress, endothelial dysfunction and neurotoxicity in Wistar rats

“…Earlier literature on donepezil suggests that in addition to its usefulness in dementia of Alzheimer's disease, it also exerts a beneficial effect in different animal models of VaD (Koladiya et al 2009;. Present study data with donepezil, as positive control, is in concurrence with earlier reports from another laboratory .…”

“…for 32 days) to induce HHcy-associated endothelial dysfunction and VaD (Shah & Singh 2007;Koladiya et al 2008Koladiya et al , 2009). …”

Attenuation of vascular dementia by sodium butyrate in streptozotocin diabetic rats

“…Endothelial dysfunction has also been reported to be related to higher oxidative stress levels (Javeshghani et al 2009;Ozkul et al 2010;Weseler and Bast 2010). Moreover, in our earlier studies, we have demonstrated that vascular endothelial dysfunction in addition to impairment of memory and oxidative stress produces rise in brain AChE activity (Koladiya et al 2008(Koladiya et al , 2009. Furthermore, very recently we have reported that single diabetogenic dose of STZ produces vascular dementia manifested in terms of endothelial dysfunction, memory impairment as well as brain oxidative stress and rise in brain AChE activity of rats.…”

“…Acetylcholinesterase inhibitors are the main class of drugs which are frequently used for the management of memory deficits. In our previous reports, we have demonstrated that donepezil, in addition to its usefulness in dementia of AD , also exerts a beneficial effect in different animal models of vascular dementia (Koladiya et al 2008(Koladiya et al , 2009Sharma and Singh 2010). Donepezil is already in clinical use for management of dementia of AD, and hence in the present study it has been used as a positive control.…”

Pitavastatin and 4-Hydroxy-3-Methoxyacetophenone (HMAP) Reduce Cognitive Dysfunction in Vascular Dementia During Experimental Diabetes

“…Endothelial dysfunction (vascular defects) has also documented to be related to higher oxidative stress levels [53][54][55]. Further, vascular defects have also been reported to produce rise in brain AChE activity [24,56]. Therefore, the noted memory impairment and various biochemical abnormalities in this study are probably linked to STZ diabetes induced endothelial dysfunction.…”