The anti-Alzheimer effect of telmisartan in a hyperglycemic ovariectomized rat model; role of central angiotensin and estrogen receptors

The central renin angiotensin system (RAS) is implicated in Alzheimer's disease (AD). Here, induction of experimental AD simulation was performed by D-galactose (D-Gal) injection to ovariectomized (OVX) rats fed on high fat high fructose diet (HFFD). Telmisartan administration to OVX/HFFD/D-Gal rats lowered the expression of hippocampal angiotensin 1 and 2 receptors and glucose transporter 2 in addition to lowering of the peripheral and central glucose levels. Furthermore, it improved cognitive impairment and suppressed hippocampal amyloidogenic markers including amyloid-beta level, phosphorylated tau protein and beta site amyloid precursor protein cleaving enzyme 1 expression, while elevated levels of insulin degrading enzyme and recovered permeability of blood brain barrier (BBB). In addition, it inhibited hippocampal oxido-nitrosative stress as well as neuroinflammatory and apoptotic biomarkers. Telmisartan improved memory and cognitive impairment as shown in the behavioral Morris water maze, Y-maze, novel object recognition and open field tests in addition to amelioration of depressive like behavior as shown in forced swimming test. Histopathological examination of brain and immune expression of glial fibrillary acidic protein were also improved together with astrogliosis improvement. In conclusion, telmisartan improved memory and cognitive impairment, recovered amyloidogenesis-hyperglycemic axis, astrogliosis, integrity of BBB, memory deficit and oxidonitrosative stress induced in OVX/HFFD/D-Gal rats. •Efficient induction of Alzheimer's disease (AD) simulation could be performed in OVX rats fed on HFFD exposed to D-gal.•AD progression is related to disturbed glycemic control, central RAS activity and central estrogenic activity.•Telmisartan showed efficient protective effects on experimental AD model concerning behavioral and biochemical evidences.•Modulation of central RAS and ER in addition to improvement of glycemic control may explain telmisartan effects.•Suppression of neuronal apoptosis, inflammation and oxidative stress may also explain telmisartan beneficial effects.