Marked prevention of ischemic brain injury by Neu2000, an NMDA antagonist and antioxidant derived from aspirin and sulfasalazine.

Neurotech Pharmaceuticals Co., Ajou University School of Medicine, Suwon, Gyeonggido, South Korea.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.34). 07/2007; 27(6):1142-51. DOI: 10.1038/sj.jcbfm.9600418
Source: PubMed

ABSTRACT Excitotoxicity and oxidative stress mediate neuronal death after hypoxic-ischemic brain injury. We examined the possibility that targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress would result in enhanced neuroprotection against hypoxic-ischemia. 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000) was derived from aspirin and sulfasalazine to prevent both NMDA neurotoxicity and oxidative stress. In cortical cell cultures, Neu2000 was shown to be an uncompetitive NMDA receptor antagonist and completely blocked free radical toxicity at doses as low as 0.3 micromol/L. Neu2000 showed marked neuroprotection in a masked fashion using histology and behavioral testing in two rodent models of focal cerebral ischemia without causing neurotoxic side effects. Neu2000 protected against the effects of middle cerebral artery occlusion, even when delivered 8 h after reperfusion. Single bolus administration of the drug prevented gray and white matter degeneration and spared neurologic function for over 28 days after MACO. Neu2000 may be a novel therapy for combating both NMDA receptor-mediated excitotoxicity and oxidative stress, the two major routes of neuronal death in ischemia, offering profound neuroprotection and an extended therapeutic window.

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    ABSTRACT: Persistent neurobehavioral deficits and brain changes need validation for brain restoration. Two hours middle cerebral artery occlusion (tMCAO) or sham surgery was performed in male Sprague-Dawley rats. Neurobehavioral and cognitive deficits were measured over 10 weeks included: (1) sensory, motor, beam balance, reflex/abnormal responses, hindlimb placement, forepaw foot fault and cylinder placement tests, and (2) complex active place avoidance learning (APA) and simple passive avoidance retention (PA). Electroretinogram (ERG), hemispheric loss (infarction), hippocampus CA1 neuronal loss and myelin (Luxol Fast Blue) staining in several fiber tracts were also measured. In comparison to Sham surgery, tMCAO surgery produced significant deficits in all behavioral tests except reflex/abnormal responses. Acute, short lived deficits following tMCAO were observed for forelimb foot fault and forelimb cylinder placement. Persistent, sustained deficits for the whole 10 weeks were exhibited for motor (p<0.001), sensory (p<0.001), beam balance performance (p<0.01) and hindlimb placement behavior (p<0.01). tMCAO produced much greater and prolonged cognitive deficits in APA learning (maximum on last trial of 604±83% change, p<0.05) but only a small, comparative effect on PA retention. Hemispheric loss/atrophy was measured 10 weeks after tMCAO and cross-validated by two methods (e.g., almost identical % ischemic hemispheric loss of 33.4±3.5% for H&E and of 34.2±3.5% for TTC staining). No visual dysfunction by ERG and no hippocampus neuronal loss were detected after tMCAO. Fiber tract damage measured by Luxol Fast Blue myelin staining intensity was significant (p<0.01) in the external capsule and striatum but not in corpus callosum and anterior commissure. In summary, persistent neurobehavioral deficits were validated as important endpoints for stroke restorative research in the future. Fiber myelin loss appears to contribute to these long term behavioral dysfunctions and can be important for cognitive behavioral control necessary for complex APA learning.
    PLoS ONE 03/2013; 8(3):e57503. · 3.53 Impact Factor
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    ABSTRACT: The April 3, 2010 earthquake along the Pernicana fault (Mt. Etna -Italy): analysis of satellite and in situ ground deformation data integrated by the SISTEM approach (3) Istituto Nazionale di Geofisica e Vulcanologia, Oss. Vesuviano, v. Diocleziano 328, Napoli, Italy, (4) GAMMA Remote Sensing, CH-3073 Gümligen, Switzerland, (5) Ecole Normale Supérieure, Laboratoire de Géologie, UMR-CNRS 8538, 24 Rue Lhomond, 75005 Paris Etna is worldwide known as one of the most studied and monitored active volcanoes. Flank instability along the eastern and southern portion of Mt. Etna has been observed and measured thanks to geodetic networks and InSAR data analysis. The spreading area is bordered to the north by the east-west Pernicana Fault System (PFS) which dynamic is often linked with the eruptive activity, as recently observed during the 2002-2003 eruption. A seismic sequence occurred since April 2-3, 2010, along the PFS with two very shallow (a few hundred meters) mainshocks of magnitude 3.6 and 3.5. Explosions and ash emissions at the summit craters followed this swarm and culminated some days later (April 7-8). Just after the earthquake, specific GPS surveys were carried out aimed at monitoring the eastern part of the Pernicana fault, and the leveling route on the northeastern flank of the volcano was also surveyed. Trying to investigate the deformation occurred along the PFS during the events of April 3rd 2010, we performed a DInSAR (Differential Interferometric Synthetic Aperture Radar) analysis of ascending and descending Envisat, and of ascending ALOS-PALSAR images encompassing the date of the earthquake. The Envisat interferograms show very intense but local deformation on the Envisat ascending data and a low signal for the descending geometry, close to the Pernicana fault trace. This is probably due to the oblique normal/left-lateral kinematics of the PFS (as deduced also by GPS and leveling data), indeed both vertical (lowering) and horizontal (eastwards) components of motion produce a strong stretching of the LOS (Line Of Sight) distance for ascending geometry, while the two components act in opposite ways for the descending geometry, resulting in lower LOS distance variations compared to the ascending data set. We analyzed also the ALOS pair referring to 21/02/2010 – 08/04/2010 time and acquired along the ascending track number 638. The ALOS interferogram clearly show three fringes corresponding to roughly 35 cm of LOS displacement. The preliminary modeling of the interferograms agree with the seismic information (very shallow faulting, seismic moment) and show that the medium behave elastically. In order to investigate the ground deformation pattern associated with this event, an application of the novel SISTEM (Simultaneous and Integrated Strain Tensor Estimation from geodetic and satellite deformation Mea-surements) approach is presented here. To achieve higher accuracy and get better constraint of the 3D components of the displacements, we improved the standard formulation of SISTEM approach, based on the GPS and a single DInSAR sensor, in order to take into account all the available dataset (GPS, leveling, ascending and descending ENVISAT C-Band interferograms and the ALOS L-Band data). The 3D displacement maps obtained using the SISTEM approach well show the kinematics of the PFS, and are able to reconstruct also the ground deformation affecting the whole investigated area, defining the movements of the north-eastern flank of the volcano. These results, which provide an accurate spatial characterization of ground deformation, are hence promising for future studies aimed at improving the knowledge about the kinematics of the active faults of Mt. Etna.
    EGU General Assembly 2011; 12/2011
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    ABSTRACT: Neu2000 (NEU; 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid), a recently developed derivative of acetylsalicylic acid and sulfasalazine, potently protects against neuronal cell death following ischemic brain injury by antagonizing NMDA receptor-mediated neuronal toxicity and oxidative stress. However, it has yet to be determined whether NEU can attenuate hypoxia-induced impairment of neuronal electrical activity. In this study, we carried out extracellular recordings of hippocampal slices in order to investigate the effects of NEU on the electrical activity of neurons exposed to a hypoxic insult (oxygen and glucose deprivation). NEU prominently suppressed hypoxia-induced impairment of neuronal activity in a concentration-dependent manner. NEU, at a low dose (1 μM), competently depressed the hypoxia-induced convulsive activity in a manner similar to trolox. Furthermore, high concentrations of NEU (50 μM) markedly abolished all hypoxia-mediated impairment of neuronal activity and accelerated the slow recovery of neuronal activity more efficiently than ifenprodil and APV. These results suggest that NEU attenuates hypoxia-induced impairment of neuronal activity more potently than the antioxidant, trolox, and the NMDA receptor antagonists, ifenprodil and APV. We propose that NEU is a striking pharmacological candidate for neuroprotection against hypoxia because of its defensive action on hypoxia-mediated impairment of electrical neurotransmission as well as its neuroprotective action against neuronal cell death induced by exposure to pathological hypoxic conditions.
    Archives of Pharmacal Research 06/2013; · 1.75 Impact Factor

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