Cognitive Deficit in Amyloid-β–Injected Mice Was Improved by Pretreatment With a Low Dose of Telmisartan Partly Because of Peroxisome Proliferator-Activated Receptor-γ Activation

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2009-10, Vol.54 (4), p.782-787
• Main Authors: Tsukuda, Kana, Mogi, Masaki, Iwanami, Jun, Min, Li-Juan, Sakata, Akiko, Jing, Fei, Iwai, Masaru, Horiuchi, Masatsugu
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alzheimer Disease - chemically induced; Alzheimer Disease - prevention & control; Amyloid beta-Peptides - administration & dosage; Amyloid beta-Peptides - adverse effects; Amyloid beta-Peptides - metabolism; Angiotensin II Type 1 Receptor Blockers - administration & dosage; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Anilides - pharmacology; Animals; Arterial hypertension. Arterial hypotension; Benzimidazoles - administration & dosage; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Benzoates - administration & dosage; Benzoates - pharmacology; Benzoates - therapeutic use; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cerebellum - blood supply; Cerebellum - metabolism; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cognition Disorders - chemically induced; Cognition Disorders - prevention & control; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Maze Learning - drug effects; Medical sciences; Mice; Mice, Inbred Strains; Nitric Oxide Synthase Type II - metabolism; PPAR gamma - antagonists & inhibitors; PPAR gamma - metabolism; Regional Blood Flow - drug effects; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.109.136879

The pathological hallmark of Alzheimer disease is deposition of amyloid-β protein (Aβ) in the brain. Telmisartan is a unique angiotensin II receptor blocker with peroxisome proliferator-activated receptor-γ (PPAR-γ)–stimulating activity. Activation of PPAR-γ is expected to prevent inflammation and Aβ accumulation in the brain. We investigated the possible preventive effect of telmisartan on cognitive decline in an Alzheimer disease mouse model via PPAR-γ activation. Here, male ddY mice underwent ICV injection of Aβ 1-40. Cognitive function was evaluated by the Morris water maze test. A low dose of telmisartan (0.35 mg/kg per day) was administered in drinking water with or without GW9662, a PPAR-γ antagonist. Cerebral blood flow was evaluated by laser speckle flowmetry. Inflammatory cytokine levels were measured by quantitative RT-PCR. Aβ 1-40 ICV injection significantly impaired cognitive function. Pretreatment with telmisartan improved this cognitive decline to a similar level to that in control mice. Cotreatment with GW9662, a PPAR-γ antagonist, attenuated this telmisartan-mediated improvement of cognition. Treatment with telmisartan enhanced cerebral blood flow and attenuated the Aβ-induced increase in expression of cytokines, such as tumor necrosis factor-α and inducible NO synthase in the brain. Interestingly, coadministration of GW9662 cancelled these beneficial effects of telmisartan. Aβ 1-40 concentration in the brain was significantly decreased by treatment with telmisartan, whereas administration of GW9662 attenuated the decrease in telmisartan-mediated Aβ 1-40 concentration. Taken together, our findings suggest that even a low dose of telmisartan had a preventive effect on cognitive decline in an Alzheimer disease mouse model, partly because of PPAR-γ activation.