Endothelin B (ETB) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ETB receptors stimulation using a highly specific agonist, IRL-1620, to treat CNS disorders. In a rat model of cerebral ischemia intravenous administration IRL-1620 significantly reduced infarct volume and improved neurological and motor functions compared to control. This improvement, in part, is due to an increase in neuroregeneration. We also investigated the role of IRL-1620 in animal models of Alzheimer’s disease (AD). IRL-1620 improved learning and memory, reduced oxidative stress and increased VEGF and NGF in Aβ treated rats. IRL-1620 also improved learning and memory in an aged APP/PS1 transgenic mouse model of AD. These promising findings prompted us to initiate human studies. Successful chemistry, manufacturing and control along with mice, rat and dog toxicological studies led to completion of a human Phase I study in healthy volunteers. We found that a dose of 0.6 μg/kg of IRL-1620 can be safely administered, three times every four hours, without any adverse effect. A Phase II clinical study with IRL-1620 has been initiated in patients with cerebral ischemia and mild to moderate AD., A. Gulati, M. G. Hornick, S. Briyal, M. S. Lavhale., and Seznam literatury
Alzheimer's Disease (AD) is the most frequent form of degenerative dementia and its early diagnosis is essential for effective treatment. Functional imaging modalities including Single Photon Emission Computed Tomography (SPECT) are often used with such an aim. However, conventional evaluation of SPECT images relies on manual reorientation and visual evaluation of tomographic slices which is time consuming, subjective and therefore prone to error. Our aim is to show an automatic Computer-Aided Diagnosis (CAD) system for improving the early detection of the AD. For this purpose, affine invariant descriptors of 3D SPECT image can be useful. The method consists of four steps: evaluation of invariant descriptors obtained using spherical harmonic analysis, statistical testing of their significance, application of regularized binary index models, and model verification via leave-one-out cross-validation scheme. The second approach is based on Support Vector Machine (SVM) classifier and visualization with use of self-organizing maps. Our approaches were tested on SPECT data from 11 adult patients with definite Alzheimer's disease and 10 adult patients with Amyotrophic Lateral Sclerosis (ALS) who were used as controls. A significant difference between SPECT spherical cuts of AD group and ALS group was both visually and numerically evaluated.
The recently described slow oscillations of amplitude of theta and alpha waves of the EEG (with a frequency below 0.08 Hz) in healthy subjects are attributed to the autonomic nervous system with control at the brain stem level. In the present pilot study, the slow brain rhythms were analyzed in a patient with Alzheimer’s disease and were compared to a healthy subject. Dynamic analysis of the EEG was performed using time-frequency mapping which gives simultaneous time and frequency representation of the brain signal. This method comprises a transform of the filtered EEG signal into its analytic form and application of the Wigner distribution modified by time and frequency smoothing. It has been shown that the envelope of both theta and alpha activities oscillates at 0.04 Hz and 0.07 Hz in the healthy subject and at 0.03 Hz and 0.06 Hz in a patient with Alzheimer’s disease. The amplitude of the slow oscillations of theta activity was substantially higher in the patient with Alzheimer’s disease as compared with the healthy subject. It is being proposed that the increase of slow brain rhythms in the patient with Alzheimer’s disease reflects an abnormal activity of the autonomic nervous system. However, the underlying pathophysiological mechanisms need to be further studied.
Increased oxidative stress in the brain during the course of Alzheimer’s disease (AD) leads to an imbalance of antioxidants and formation of free radical reaction end-products which may be detected in blood as fluorescent lipofuscin-like pigments (LFPs). The aim of this study was to evaluate and compare LFPs with plasma selenium concentrations representing an integral part of the antioxidant system. Plasma samples from subjects with AD dementia (ADD; n=11), mild cognitive impairment (MCI; n=17) and controls (n=12), were collected. The concentration of selenium was measured using atomic absorption spectroscopy. LFPs were analyzed by fluorescence spectroscopy and quantified for different fluorescent maxima and then correlated with plasma selenium. Lower levels of selenium were detected in MCI and ADD patients than in controls (P=0.003 and P=0.049, respectively). Additionally, higher fluorescence intensities of LFPs were observed in MCI patients than in controls in four fluorescence maxima and higher fluorescence intensities were also observed in MCI patients than in ADD patients in three fluorescence maxima, respectively. A negative correlation
between selenium concentrations and LFPs fluorescence was observed in the three fluorescence maxima. This is the first study focused on correlation of plasma selenium with specific lipofuscin-like products of oxidative stress in plasma of patients with Alzheimer´s disease and mild cognitive impairment.