Ameliorative Effects of Telmisartan on the Inflammatory Response and Impaired Spatial Memory in a Rat Model of Alzheimer’s Disease Incorporating Additional Cerebrovascular Disease Factors

Abstract

Telmisartan, an angiotensin type 1 receptor blocker, is used in the management of hypertension to control blood pressure. In addition, telmisartan has a partial agonistic effect on peroxisome proliferator activated receptor γ (PPARγ). Recently, the effects of telmisartan on spatial memory or the inflammatory response were monitored in a mouse model of Alzheimer's disease (AD). However, to date, no studies have investigated the ameliorative effects of telmisartan on impaired spatial memory and the inflammatory response in an AD animal model incorporating additional cerebrovascular disease factors. In this study, we examined the effect of telmisartan on spatial memory impairment and the inflammatory response in a rat model of AD incorporating additional cerebrovascular disease factors. Rats were subjected to cerebral ischemia and an intracerebroventricular injection of oligomeric or aggregated amyloid-β (Aβ). Oral administration of telmisartan (0.3, 1, 3 mg/kg/d) seven days after ischemia and Aβ treatment resulted in better performance in the eight arm radial maze task in a dose-dependent manner. Telmisartan also reduced tumor necrosis factor α mRNA expression in the hippocampal region of rats with impaired spatial memory. These effects of telmisartan were antagonized by GW9662, an antagonist of PPARγ. These results suggest that telmisartan has ameliorative effects on the impairment of spatial memory in a rat model of AD incorporating additional cerebrovascular disease factors via its anti-inflammatory effect. Key words telmisartan; tumor necrosis factor α; Alzheimer disease; inflammatory; ratThe epidemiological survey findings indicate that the Alzheimer's disease (AD) rapidly progresses in case of which elderly people have a history of lifestyle-related diseases such as hypertension, lipid abnormality, diabetes and cerebrovascular disease (e.g., brain infarction). [1][2][3][4][5] The clinical report also indicates that the AD patients with a history of cerebrovascular disease exhibit a more rapid progression of dementia.6) Overall, 47% of demented participants in that clinical study had AD and/or additional brain infarcts, suggesting that the mixed form of such dementia may be very common in the elderly.Based on the context of the above clinical studies, we have developed several AD-like animal models incorporated additional lifestyle-related disease factors, where the model animals in various clinical states were obtained by imposing the altering aggregate morphology of amyloid-β (Aβ) on naïve animals. 7,8) Since theses animal models reveal that administration of aggregated Aβ could induce neuronal cell death and spatial memory impairment, we have used them to evaluate the related-drug efficacy. Our pharmacological study indicates that the hypoxia treatment enhances Aβ-induced apoptosis in cultured hippocampal neurons. 9)

Oridonin ameliorates neuropathological changes and behavioural deficits in a mouse model of cerebral amyloidosis

“…Recently, many experimental treatments with anti-inflammatory agents were tested in animal models of AD as well, such as: CHF5074, a non-steroidal anti-inflammatory drug [33]; aspirintriggered LXA4 [34]; telmisartan [35]; cyclooxygenase-1 [36]; minocycline [37] and several cannabinoids [5]. They inhibited or modulated microglial activation, attenuated neuroinflammatory reaction, reduced AD-like pathology, some of them also improved cognitive deficits in transgenic mouse models of AD, similar as Oridonin's effect observed in our present study.…”

Investigation of the effect of telmisartan on experimentally induced peripheral nerve injury in rats

“…Previous studies also showed that, unlike other AT1 receptor antagonists, telmisartan activates PPAR-γ receptors [14,15]. Positive effects of telmisartan on the central nervous system have also been demonstrated [16]. Jaggi and Singh explored the potential of telmisartan in chronic constriction injury-induced neuropathic pain in rats [17].…”

Effect of hachimijiogan on memory impairment induced by beta‐amyloid combined with cerebral ischemia in rats

“…Aggregated Aβ was prepared as previously described . Aβ42 peptides were purchased from Anaspec (Fremont, CA, USA), dissolved in HEPES‐buffered solution to a final concentration of 10 µmol/L, and incubated at 37°C for 7 days.…”

“…The Aβ + CI rats (water maze task, n = 24; eight‐arm radial maze task, n = 38) were prepared by combining intracerebroventricular Aβ injection with transient CI as previously described . Rats were anesthetized with sodium pentobarbital.…”

“…Cerebrovascular disease (CVD) is commonly found in patients with AD . We previously showed that the combination of intracerebroventricular Aβ injection and transient cerebral ischemia (CI) induces memory impairment in rats . The aim of this study was therefore to investigate the effect of HJG on memory impairment in rats treated with Aβ + CI.…”