Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia.

Blood glutamate scavenging is a novel and attractive protecting strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. Glutamate oxaloacetate transaminase 1 (GOT1) activation by means of oxaloacetate administration has been used to reduce the glutamate concentration in the blood. However, the protective effect of the administration of the recombinant GOT1 (rGOT1) enzyme has not been yet addressed in cerebral ischemia. The aim of this study was to analyze the protective effect of an effective dose of oxaloacetate and the human rGOT1 alone and in combination with a non-effective dose of oxaloacetate in an animal model of ischemic stroke. Sixty rats were subjected to a transient middle cerebral artery occlusion (MCAO). Infarct volumes were assessed by magnetic resonance imaging (MRI) before treatment administration, and 24 h and 7 days after MCAO. Brain glutamate levels were determined by in vivo MR spectroscopy (MRS) during artery occlusion (80 min) and reperfusion (180 min). GOT activity and serum glutamate concentration were analyzed during the occlusion and reperfusion period. Somatosensory test was performed at baseline and 7 days after MCAO. The three treatments tested induced a reduction in serum and brain glutamate levels, resulting in a reduction in infarct volume and sensorimotor deficit. Protective effect of rGOT1 supplemented with oxaloacetate at 7 days persists even when treatment was delayed until at least 2 h after onset of ischemia. In conclusion, our findings indicate that the combination of human rGOT1 with low doses of oxaloacetate seems to be a successful approach for stroke treatment.

Increased levels of circulating endothelial progenitor cells in patients with ischaemic stroke treated with statins during acute phase.

BACKGROUND AND PURPOSE: Endothelial progenitor cells (EPCs) have been suggested to be a therapeutic option in ischaemic stroke. Our aim was to study whether statin treatment during acute phase could increase circulating EPCs after acute ischaemic stroke. METHODS: We studied 48 patients with a first-ever non-lacunar ischaemic stroke (<12 h from stroke onset). Sixteen patients received statin treatment (20 mg atorvastatin/day) during the first 4 days. We defined the EPC increment during the first week as the difference in the number of early outgrowth colony-forming unit-endothelial cell (CFU-EC) between day 7 and at admission (previous to atorvastatin treatment). Serum levels of vascular endothelial growth factor and active matrix metalloproteinase 9 (determined by ELISA), and nitric oxide metabolites (NOx) (determined by high-performance liquid chromatography) were measured at admission, 24 and 72 h, and day 7. RESULTS: Colony-forming unit-endothelial cells were similar at baseline between patients treated (n = 16) and non-treated (n = 32) with statins (10.1 ± 3.9 vs. 7.9 ± 6.9 CFU-EC, P = 0.223). However, patients treated with statins showed a higher EPC increment (24.0 ± 17.3 vs. 6.0 ± 17.8 CFU-EC, P = 0.002) during the first week. An EPC increment ≥ 4 CFU-EC predicted with the highest sensitivity (88%) and specificity (92%) the probability of good outcome (area under the curve 0.903, P < 0.0001). Statin treatment (OR, 13.1; CI 95%, 2.2-76.9, P = 0.004) was independently associated with an EPC increment ≥ 4 CFU-EC after adjustment for confounder factors, but this association was lost when adjusting for NOx levels. CONCLUSIONS: Statin treatment for 4 days may increase circulating EPC levels, probably by NO-related mechanisms.

Comparación de la lesión producida en tres modelos animales de isquemia cerebral focal permanente mediante resonancia magnética / Comparison of the lesion produced by permanent focal cerebral ischaemia in three animal models using magnetic resonance imaging

Introducción. Los modelos animales de isquemia cerebral son indispensables en la investigación de la patología cerebrovascular. Actualmente, no existe un modelo experimental que refleje perfectamente la fisiopatología del ictus, por lo que la selección de éste es fundamental para una interpretación correcta de los resultados obtenidos. Objetivo. Caracterizar la evolución temporal de tres modelos comunes de isquemia cerebral focal permanente mediante resonancia magnética. Materiales y métodos. Treinta ratas macho Sprague-Dawley se dividieron en tres grupos, cada uno sometido a los siguientes modelos quirúrgicos: sutura intracraneal de la arteria cerebral media (ACM), electrocoagulación de la ACM y oclusión intraluminal de la ACM. Cada animal se sometió a una exploración por resonancia magnética los días 1, 2, 3, 4, 7 y 14 tras la cirugía. A partir de imágenes adquiridas con secuencias potenciadas en T2 se calcularon tanto el volumen de lesión como el grado de edema. Resultados. El modelo intraluminal presentó mayor volumen de infarto (media: 297 ± 163 mm3 de volumen máximo) y mayor edema (media: 17 ± 9% de edema máximo) frente al modelo de sutura intracraneal (178 ± 62 mm3 y 9 ± 6%, respectivamente) y electrocoagulación (181 ± 45 mm3 y 9 ± 6%, respectivamente). Discusión. Pese a presentar una mayor mortalidad (28%), el modelo de oclusión intraluminal de la ACM es el más adecuado para estudios a largo plazo al no precisar craneotomía, al contrario que los modelos transcraneales. El modelo de oclusión por electrocoagulación muestra una región cerebral de lesión no isquémica y una evolución de la lesión diferente a los otros dos modelos (AU)

Introduction. Animal models of brain ischemia are essential to reveal the full aspects of cerebrovascular pathologies. The perfect animal model that reflects every aspect of stroke pathophysiology does not exist, hence there is a need for a proper selection of the animal model in order to interpret properly the results from experimental research. Aim. To characterize and compare the temporal evolution of three common models of focal brain ischemia using magnetic resonance imaging (MRI) techniques. Materials and methods. Thirty Sprague-Dawley rats were distributed into three groups, each of them submitted to one of the following surgery procedures: middle cerebral artery (MCA) intracranial suture, MCA electrocoagulation, and MCA intraluminal suture. Each rat was subjected to an MRI study at days 1, 2, 3, 4, 7 and 14 post-surgery. T2 weighted images were obtained in order to calculate both lesion volumes and edema. Results. Infarct volume and edema were maximal for the intraluminal model (peaks of mean 297 ± 163 mm3 and mean 17 ± 9%, respectively) compared to intracranial suture (178 ± 62 mm3 and 9 ± 6%, respectively) and electrocoagulation (181 ± 45 mm3 and 9 ± 6%, respectively) models. Discussion. The intraluminal occlusion of the MCA model, although yields in the highest mortality rate (28%), it is the more suitable for long term studies, mainly because of the absence of craniotomy. In the electrocoagulation model a non ischemic lesion region is observed which leads to an abnormal lesion evolution as compared with the other two models (AU)

[Comparison of the lesion produced by permanent focal cerebral ischaemia in three animal models using magnetic resonance imaging]. / Comparacion de la lesion producida en tres modelos animales de isquemia cerebral focal permanente mediante resonancia magnetica.

INTRODUCTION: Animal models of brain ischemia are essential to reveal the full aspects of cerebrovascular pathologies. The perfect animal model that reflects every aspect of stroke pathophysiology does not exist, hence there is a need for a proper selection of the animal model in order to interpret properly the results from experimental research. AIM: To characterize and compare the temporal evolution of three common models of focal brain ischemia using magnetic resonance imaging (MRI) techniques. MATERIALS AND METHODS: Thirty Sprague-Dawley rats were distributed into three groups, each of them submitted to one of the following surgery procedures: middle cerebral artery (MCA) intracranial suture, MCA electrocoagulation, and MCA intraluminal suture. Each rat was subjected to an MRI study at days 1, 2, 3, 4, 7 and 14 post-surgery. T2 weighted images were obtained in order to calculate both lesion volumes and edema. RESULTS: Infarct volume and edema were maximal for the intraluminal model (peaks of mean 297 ± 163 mm3 and mean 17 ± 9%, respectively) compared to intracranial suture (178 ± 62 mm3 and 9 ± 6%, respectively) and electrocoagulation (181 ± 45 mm3 and 9 ± 6%, respectively) models. DISCUSSION: The intraluminal occlusion of the MCA model, although yields in the highest mortality rate (28%), it is the more suitable for long term studies, mainly because of the absence of craniotomy. In the electrocoagulation model a non ischemic lesion region is observed which leads to an abnormal lesion evolution as compared with the other two models.