Background: Statins, HMG-CoA reductase inhibitors, are widely prescribed drugs for dyslipidemias. Recent studies have indicated number of cholesterol independent actions of statins including their beneficial effects on vascular endothelial dysfunction and memory deficits associated with dementia of Alzheimer's type. However the potential of statins in dementia of vascular origin still remains to be explored. Therefore, the present study has been designed to investigate the effect of Atorvastatin & Pitavastatin on vascular endothelial dysfunction associated memory deficits in rats. In this study L-Methionine induced vascular dementia was assessed by Morris water-maze (MWM) test. Biochemical analysis was also performed to unfold possible mechanism of statins mediated modulation of vascular dementia.

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.

Endothelium forms an innermost lining of blood vessel and it regulates the vascular tone and permeability. A healthy vascular endothelium is antiatherogenic in nature because of its properties such as inhibition of platelet aggregation, adhesion cascades, smooth muscle cell proliferation and leukocyte adhesion. Vascular endothelial dysfunction (VED) is associated with reduced synthesis and release of nitric oxide, proinflammatory and prothrombotic properties followed by diminished vasodilation. VED has been implicated in the pathogenesis of artherosclerosis, hypertension, myocardial infarction, heart failure, renal failure and stroke. Various pharmacological interventions such as angiotensin converting enzyme (ACE) inhibitors, statins, insulin sensitizers, L-arginine as well as agents that target endothelial nitric oxide synthase (eNOS) "coupling" such as folates or tetrahydrobiopterin (BH4) have been noted to improve the function of vascular endothelium. In this review, we discussed various recently developed pharmacological interventions to improve the function of endothelium. Moreover, the novel targets sites involved in the pathogenesis of vascular endothelial dysfunction have been delineated.