Effect of Aβ -promoting drugs treatment on blood pressure and amyloid neuropathology in Tg2576 mice.

<p>(A and D) Measurements of systolic, diastolic blood pressure, and mean arterial blood pressure (MAP) in response to ∼4 weeks of drug treatments. (B and E) Assessment of Aβ1-42 and Aβ1-40 peptide concentrations in the brain of drug treated mice <i>vs.</i> the control mice. (C and F) Assessment of Aβ1-42 and Aβ1-40 in peripheral blood of drug treated mice <i>vs.</i> the control mice. Values represents group mean values (±SEM); n = 3–5 mice per group. **P<0.01, *P<0.05, 2-tailed student t-test.</p

Effect of chronic propranolol treatment on spatial memory and neuropathology in Tg2576 mice.

<p>(A-D) The influence of chronic propranolol treatment on Aβ related spatial memory in Tg2576 mice by Morris water maze test (A) Visible trial (B) Swimming speed (C) Hidden platform learning acquisition, latency score represents time taken to escape to the platform from the water. (D) Probe trial. Percent of time in quadrant is calculated as the ratio of time spent in the target quadrant area relative to the time spent in the rest of the pool. (E-F) The influence of chronic propranolol treatment wild type mice by Morris water maze test: (E) Hidden platform learning acquisition (F) Probe trial. (G-H) Brain and plasma levels of total Aβ1-40 and Aβ1-42 peptides following chronic propranolol treatment. Values represent group mean ± SEM, n = 7–8 per group.</p

Short-term in vivo treatment dosage conversion in Tg2576 mice.

<p>The dosage recommended for hypertension treatment in humans is listed as prescribed clinical dose. The equivalent dosage in animals is calculated using FDA criteria for converting drug equivalent dosages across species, based on body surface area <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065232#pone.0065232-ReaganShaw2" target="_blank">[39]</a>. The mice equivalent dosage was used in the short-term treatment.</p

Effect of chronic nicardipine treatment on spatial memory and neuropathology in Tg2576 mice.

<p>(A-C) The influence of chronic nicardipine treatment on Aβ related spatial memory in Tg2576 mice by MWM test: (A) Visible trial (B) Hidden platform learning acquisition (C) Probe trial. (D-E) Brain and plasma levels of total Aβ1-40 and Aβ1-42 peptides following chronic nicardipine treatment. Values represent group mean ± SEM, n = 9–11 per group.</p

Schematic diagram of primary screening of 1600 FDA approved drugs.

<p>Schematic diagram of primary screening of 1600 FDA approved drugs.</p

115 commonly prescribed cardiovascular drugs used in screening for potential Aβ-modifying activity.

<p>The 115 cardiovascular agents were obtained as part of the Spectrum Collection from MicroSource Discovery Systems Inc. and listed in 4 pharmacological categories (source: Physician’s Desk Reference and Martindale Complete Drug Reference). Potential Aβ-modifying activity was assessed using primary cortico-hippocampal neuron cultures derived from embryonic Tg2576 AD mice and the levels of Aβ in the conditioned medium were measured and expressed as percentage of vehicle-treated control (Aβ column). In the high-throughput screening studies, 13 drugs lowered the Aβ content greater than 30% and two drugs (in bold and Italic) increased Aβ content greater than 30% compared to the vehicle controls. The 13 Aβ-lowering drugs were proceeded to a follow-up dose dependent test and the 8 drugs in bold were found to exert significant dose dependent Aβ -lowering activity in the absence of cellular toxicity. “–” indicates that the drug is toxic for primary neurons at 100 µM.</p

Effect of Aβ-lowering drug treatment on blood pressure and amyloid neuropathology in Tg2576 mice.

<p>(A–F) Measurements of systolic, diastolic blood pressure, and mean arterial blood pressure (MAP) and heart beat (pulse) in response to ∼4 weeks of drug treatments. (G-L) Assessment of Aβ1-42 and Aβ1-40 peptide concentrations in the brain of drug treated mice <i>vs.</i> the control mice. (M-R) Assessment of Aβ1-42 and Aβ1-40 in peripheral blood of drug treated mice <i>vs.</i> the control mice. Blood pressure determination for each animal was calculated as the mean of 10 individual measurements. Values represents group mean values (<u>+</u>SEM); n = 3–5 mice per group. **P<0.01, *P<0.05, 2-tailed student t-test.</p

Effect of short-term in vivo on body weight and liquid consumption in Tg2576 mice.

<p>Animals were treated with the anti-hypertensive drugs for four weeks and body weight and liquid consumption were monitored weekly. Data presented here are the end point body weight and the average liquid consumption throughout the study.</p>*<p>P<0.05, 2-tailed student t-test, n = 3–5 for each treatment group.</p