Effects of NK-4 in a Transgenic Mouse Model of Alzheimer's Disease

Beta-amyloid (Aβ) peptides are considered to play a major role in the pathogenesis of Alzheimer's disease (AD) and molecules that can prevent pathways of Aβ toxicity may be potential therapeutic agents for treatment of AD. We have previously reported that NK-4, a cyanine photosensitizing dye, displays neurotrophic and antioxidant activities. In this study, we report the effects of NK-4 on the toxicity of Aβ and on cognitive function and Aβ concentration in a transgenic mouse model of AD (Tg2576). In vitro, NK-4 effectively protected neuronal cells from toxicity induced by Aβ. In addition, it displayed profound inhibitory activities on Aβ fibril formation. In vivo, Tg2576 mice received an intraperitoneal injection at 100 or 500 µg/kg of NK-4 once a day, five times a week for 9 months. Administration of NK-4 to the mice attenuated impairment of recognition memory, associative memory, and learning ability, as assessed by a novel object recognition test, a passive avoidance test, and a water maze test, respectively. NK-4 decreased the brain Aβ concentration while increasing the plasma amyloid level in a dose-dependent manner. NK-4 also improved memory impairments of ICR mice induced by direct intracerebroventricular administration of Aβ. These lines of evidence suggest that NK-4 may affect multiple pathways of amyloid pathogenesis and could be useful for treatment of AD

Neurotrophic Effects of a Cyanine Dye via the PI3K-Akt Pathway: Attenuation of Motor Discoordination and Neurodegeneration in an Ataxic Animal Model

BACKGROUND: Neurotrophic factors may be future therapeutic agents for neurodegenerative disease. In the screening of biologically active molecules for neurotrophic potency, we found that a photosensitizing cyanine dye, NK-4, had remarkable neurotrophic activities and was a potent radical scavenger. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluated the effect of NK-4 on the protection of neurons against oxidative damage and investigated the associated intracellular signaling pathways. Subsequently, we evaluated the effect of NK-4 in an animal model of neurodegeneration. In vitro, NK-4 showed dose-dependent protection of PC12 cells from toxicity induced by oxidative stress caused by hydrogen peroxide (H(2)O(2)) or 6-hydroxydopamine (6-OHDA). Comparison of extracellular signal-regulated kinase signaling pathways between treatment with NK-4 and nerve growth factor (NGF) using K252a, an inhibitor of the NGF receptor TrkA, revealed that NK-4 activity occurs independently of NGF receptors. LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, blocked the protective effect of NK-4, and NK-4 caused activation of Akt/protein kinase B, a downstream effector of PI3K. These results suggest that the neuroprotective effects of NK-4 are mediated by the PI3K-Akt signaling pathway. NK-4 treatment also attenuated stress-induced activation of SAPK/JNK, which suggests that NK-4 activates a survival signaling pathway and inhibits stress-activated apoptotic pathways independently of the TrkA receptor in neuronal cells. In vivo, administration of NK-4 improved motor coordination in genetic ataxic hamsters, as assessed by rota-rod testing. Histological analysis showed that cerebellar atrophy was significantly attenuated by NK-4 treatment. Notably, the Purkinje cell count in the treated group was threefold higher than that in the vehicle group. CONCLUSIONS/SIGNIFICANCE: These results suggest that NK-4 is a potential agent for therapy for neurodegenerative disorders based on the activation of survival signaling pathways

Automatic Recognition of Speed Limits on Speed-Limit Signs by Using Machine Learning

This study describes a method for using a camera to automatically recognize the speed limits on speed-limit signs. This method consists of the following three processes: first (1) a method of detecting the speed-limit signs with a machine learning method utilizing the local binary pattern (LBP) feature quantities as information helpful for identification, then (2) an image processing method using Hue, Saturation and Value (HSV) color spaces for extracting the speed limit numbers on the identified speed-limit signs, and finally (3) a method for recognition of the extracted numbers using a neural network. The method of traffic sign recognition previously proposed by the author consisted of extracting geometric shapes from the sign and recognizing them based on their aspect ratios. This method cannot be used for the numbers on speed-limit signs because the numbers all have the same aspect ratios. In a study that proposed recognition of speed limit numbers using an Eigen space method, a method using only color information was used to detect speed-limit signs from images of scenery. Because this method used only color information for detection, precise color information settings and processing to exclude everything other than the signs are necessary in an environment where many colors similar to the speed-limit signs exist, and further study of the method for sign detection is needed. This study focuses on considering the following three points. (1) Make it possible to detect only the speed-limit sign in an image of scenery using a single process focusing on the local patterns of speed limit signs. (2) Make it possible to separate and extract the two-digit numbers on a speed-limit sign in cases when the two-digit numbers are incorrectly extracted as a single area due to the light environment. (3) Make it possible to identify the numbers using a neural network by focusing on three feature quantities. This study also used the proposed method with still images in order to validate it

Automatic Recognition of Speed Limits on Speed-Limit Signs by Using Machine Learning

This study describes a method for using a camera to automatically recognize the speed limits on speed-limit signs. This method consists of the following three processes: first (1) a method of detecting the speed-limit signs with a machine learning method utilizing the local binary pattern (LBP) feature quantities as information helpful for identification, then (2) an image processing method using Hue, Saturation and Value (HSV) color spaces for extracting the speed limit numbers on the identified speed-limit signs, and finally (3) a method for recognition of the extracted numbers using a neural network. The method of traffic sign recognition previously proposed by the author consisted of extracting geometric shapes from the sign and recognizing them based on their aspect ratios. This method cannot be used for the numbers on speed-limit signs because the numbers all have the same aspect ratios. In a study that proposed recognition of speed limit numbers using an Eigen space method, a method using only color information was used to detect speed-limit signs from images of scenery. Because this method used only color information for detection, precise color information settings and processing to exclude everything other than the signs are necessary in an environment where many colors similar to the speed-limit signs exist, and further study of the method for sign detection is needed. This study focuses on considering the following three points. (1) Make it possible to detect only the speed-limit sign in an image of scenery using a single process focusing on the local patterns of speed limit signs. (2) Make it possible to separate and extract the two-digit numbers on a speed-limit sign in cases when the two-digit numbers are incorrectly extracted as a single area due to the light environment. (3) Make it possible to identify the numbers using a neural network by focusing on three feature quantities. This study also used the proposed method with still images in order to validate it

Left Ventricular Diastolic Function during the Normal Peripartum Period

Background:Because cardiovascular function and hemodynamics markedly change during pregnancy, our aim was to elucidate left ventricular (LV) diastolic function in pregnant women. Methods and Results:We prospectively collected the data of 397 pregnant women treated between 2012 and 2013. We evaluated their LV systolic and diastolic functions via echocardiography during the 3rd trimester (28–30 weeks’ gestation) and within 4 days of delivery. Additionally, we analyzed the cardiac geometry: relative wall thickness and LV mass index (LVMI). Diastolic dysfunction was defined as early diastolic mitral annulus velocity (e’) 15. The pregnant women were 33.7±5.0 years old and the prevalence of hypertensive disorders in pregnancy (HDP) was 4.0%. LV systolic function was preserved in all pregnant women. However, diastolic function significantly decreased after delivery (mean e’: 12.6 vs. 11.6 cm/s, P<0.0001; median E/e’ ratio: 6.4 vs. 7.3, P<0.0001). Diastolic function after delivery was associated with the prevalence of HDP (P=0.035) and was correlated with age (R=−0.17, P=0.0009) and LVMI (R=−0.30, P<0.0001). However, these changes in diastolic function remained within the normal range and only 1 woman (1/397, 0.3%) had LV diastolic dysfunction after delivery. Conclusions:LV diastolic function decreased after delivery in pregnant women but was within the normal range

A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage

Angiotensin II receptor blockers (ARBs) have a potent ability to inhibit oxidative stress and advanced glycation, in addition to their protective effects originated from blood pressure lowering and angiotensin II type 1 receptor (AT(1))-blockade. To obtain a pharmacological tool to dissect the mechanisms of ARBs' protective benefits in experimental stroke, we synthesized a novel ARB-derivative, R-147176, which is 6,700 times less potent than olmesartan in AT(1)-binding inhibition and therefore has a minimal antihypertensive effect, but retains marked inhibitory effects on oxidative stress and advanced glycation. We evaluated the effect of R-147176 (10-30 mg/kg per day), administered orally or intravenously, on brain infarct volume in transient thread occlusion and photothrombotic models in rats. The antioxidative and antiinflammatory properties were also investigated. R-147176 significantly reduced infarct volume, without influence on blood pressure, in both models. R-147176 significantly reduced the numbers of ED-1-positive cells and of TUNEL-positive cells, and protein carbonyl formation in the damaged brain. This ARB derivative, despite its significantly lower AT1 affinity and virtually no antihypertensive effect, ameliorated ischemic cerebral damage through antioxidative and antiinflammatory properties. These findings suggest potential usefulness of R-147176 as a pharmacological tool to investigate the ARBs' protective effect in experimental stroke and open new therapeutic avenues. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1665-1672; doi:10.1038/jcbfm.2009.82; published online 17 June 200

Factors associated with increased levels of brain natriuretic peptide and cardiac troponin I during the peripartum period.

BACKGROUND:We aimed to investigate the values and the changes of brain natriuretic peptide (BNP) and cardiac troponin in pregnant women. METHODS AND RESULTS:We prospectively collected the data of 405 pregnant women who were treated at Japanese general hospital between 2012 and 2013. We analyzed their laboratory data and echocardiographic findings during the third trimester (28-30 weeks' gestation) and within 4 days of delivery. In addition, we evaluated the factors associated with elevation of BNP and cardiac troponin I (cTnI) levels. The pregnant women were 33.8 ± 5.0 years old and the prevalence of pregnancy induced hypertension (PIH) and placental abnormality was 4.2% and 2.5%, respectively. BNP levels increased after delivery (13.2 pg/mL vs. 23.5 pg/mL; P <0.001), correlated with increased left ventricular diastolic dimension (P = 0.035), left atrial dimension (P <0.001), and decreased hemoglobin (P <0.001). Moreover, cTnI levels increased to over 0.015 ng/mL after delivery in 4.0% of pregnant women. In multivariate analysis, PIH (OR: 18.71, P = 0.003), placental abnormality (OR: 26.78, P = 0.007), and decreased hemoglobin after delivery (OR: 2.59, P <0.001) were the factors associated with elevated cTnI. CONCLUSIONS:BNP levels increased in association with cardiac chamber enlargement and decreased hemoglobin after delivery. Additionally, the factors affecting elevated cTnI levels were related to labor and delivery

A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia

We have developed a novel, non-toxic inhibitor of advanced glycation and oxidative stress, TM2002, devoid of effect on blood pressure. In transient focal ischemia, TM2002 significantly decreased infarct volume compared with vehicle (79.5 +/- 18.7 vs. 183.3 +/- 22.9 mm(3), p < 0.01). In permanent focal ischemia, TM2002 (2.79, 5.58, and 11.16 mg/kg twice a day) dose-dependently reduced infarct volume (242.1 +/- 32.3, 201.3 +/- 15.1, and 171.3 +/- 15.2 mm(3), respectively), and improved neurological deficits. Reduction of infarct volume is demonstrable, provided that TM2002 was administered within 1.5 h after the occlusion. To unravel TM2002's mechanism of action, we examined its in vitro effect on endoplasmic reticulum (ER) stress, using aortic smooth muscle cells isolated from ORP 150(+/-) mice and F9 Herp null mutated cells. Cell death induced by ER stress (tunicamycin or hypoxia) was dose-dependently prevented by TM2002. In vivo immunohistochemical study demonstrated a significant reduction of ORP- and TUNEL-positive apoptotic cells, especially in the penumbra. Inhibition of advanced glycation and oxidative stress was confirmed by a significantly reduced number of cells positive for advanced glycation end products and heme oxygenase-1. TM2002 reduced the levels of protein carbonyl formation in ischemic caudate. The efficacy of TM2002 is equivalent to that of a known neuroprotective agent, NXY-059. In conclusion, TM2002 significantly ameliorates ischemic cerebral damage through reduction of ER stress, advanced glycation, and oxidative stress, independently of blood pressure lowering. (c) 2007 Published by Elsevier B.V