Possible role of endothelin receptor against hyperhomocysteinemia and β-amyloid induced AD type of vascular dementia in rats.

Abstract

Vascular dementia (VaD) is considered as the second commonest form of dementia after Alzheimer's disease (AD). The study was designed to investigate the effect of endothelin receptor against β-amyloid induced AD type of vascular dementia. This disease was induced by combine administration of single ICV (intracerebroventricle) infusion of β-amyloid (Aβ) once and chronic oral administration of l-Methionine for 21 days. Bosentan (dual endothelin receptor antagonist) was administered for 21 days. Behavioral alterations were observed during different time interval of the study. Animals were killed immediately following the last behavior session. Oxidative parameters, acetylcholinesterase activity, neuro-inflammatory markers, amyloid beta levels were determined in hippocampus and cortex while serum homocysteine, serum nitrite carotid artery superoxide anion level were also determined. Endothelial function was measured on isolated carotid artery using myograph instrument. Aβ+l-Methionine showed more significant development of cognitive and vascular endothelial deficits, manifested in terms of increase in serum homocysteine level, endothelial dysfunction, impairment of learning and memory, enhanced brain acetylcholinesterase activity, marked mito-oxidative damage in rats. We have observed that l-Methionine and combination of Aβ+l-Methionine significantly enhanced Aβ level both in cortex as well as hippocampus. Treatment of bosentan attenuated Aβ+l-Methionine induced impairment of learning and memory, enhanced Aβ level, mitochondrial and endothelial dysfunction. The results of present study concluded that bosentan offers protection against β-amyloid-induced vascular dementia in rats. Endothelin receptor may be considered as a potential pharmacological target for the management of AD type of vascular dementia.