Modelo experimettal de hipoperfusión cerebral poduce déficit de la memoria y aaprendizaje y modificaciones en la expresión de genes / Experimental Model of Cerebral Hypoperfusion Produced Memory-learning Deficits, and Modifications in Gene Expression

A escala mundial, la isquemia cerebral constituye una de las principales causas de muerte, por lo que los modelos animales de isquemia cerebral son extensamente usados tanto en el estudio de la pato-fisiología del fenómeno isquémico; como en la evaluación de agentes terapéuticos con posible efecto protector o regenerador. Los objetivos de este estudio fueron examinar la presencia de daño neuronal en diferentes áreas cerebrales como consecuencia del evento isquémico; así como evaluar consecuencias de este proceder sobre los procesos de memoria-aprendizaje. Los grupos de estudios incluyeron un grupo experimental de animales isquémicos, 30 ratas a las que se les ocluyó ambas arterias carótidas comunes, y un grupo control. Fue evaluada la expresión de genes isquémicos e inflamatorios por técnicas de qPCR 24 horas post lesión, la morfología del tejido cerebral en áreas de corteza, estriado e hipocampo, siete días post lesión y los procesos de memoria y aprendizaje, 12 días post lesión. Los estudios morfológicos evidenciaron que el proceder induce la muerte de poblaciones celulares en corteza, estriado e hipocampo; la isquemia modificó la expresión los genes gfap, ho-1, il-6, il-17 e ifn-γ, lo cual puede ser utilizado como un marcador de proceso isquémico temprano. Adicionalmente, el daño isquémico causó un deterioro en la memoria espacial. Esta caracterización nos permite contar con un modelo experimental donde desarrollar futuros estudios sobre la patofisiología de los eventos isquémicos y la evaluación de estrategias terapéuticas.

Cerebral ischemia is a major cause of death, for this reason animal models of cerebral ischemia are widely used to study both the pathophysiology of ischemic phenomenon and the evaluation of possible therapeutic agents with protective or regenerative properties. The objectives of this study were to examine the presence of neuronal damage in different brain areas following the ischemic event, and assess consequences of such activities on the processes of memory and learning. The study group included an experimental group ischemic animals (30 rats with permanent bilateral occlusion of the carotids), and a control group. Was evaluated gene expression and inflammatory ischemic by qPCR techniques 24h post injury, brain tissue morphology in areas of cortex, striatum and hippocampus seven days post injury and processes of memory and learning, 12 days post injury. The morphological studies showed that the procedure induces death of cell populations in cortex, striatum and hippocampus, ischemia modified gfap gene expression and ho, il-6, il-17 and ifn-γ, which can be used as a marker of early ischemic process. Additionally, the ischemic injury caused spatial memory decline. This characterization gives us an experimental model to develop future studies on the pathophysiology of ischemic events and assessing therapeutic strategies.

Sensory-motor performance after acute glutathione depletion by L-buthionine sulfoximine injection into substantia nigra pars compacta.

Glutathione is the major antioxidant in the living cells. Its deficit has been linked to neurodegenerative disorders as Parkinson's disease but its role in the etiology of nigral degeneration and sensory-motor performance has been poorly explored. To evaluate the effect of glutathione depletion on nigro-striatal oxidative metabolism and sensory-motor performance in rats, l-buthionine sulfoximine (15 mM) or saline solution was injected into substantia nigra pars compacta (SNpc). Then, oxidative metabolism was studied 24h and 7 days later in SNpc and corpus striatum (CS). Tyrosine hydroxylase and GFAP immunohistochemistry assays were carried out at 7 days. In addition, animals were evaluated in open field, adhesive removal, staircase and traverse beam tests. Glutathione depletion induced compensatory response in catalase activity and glial response in the in SNpc and no oxidative damage was observed. However, a loss in dopaminergic cells was found. At the same time, animals with glutathione depletion have shown poor performance in behavioral tests except for staircase test. These results suggest that glutathione depletion can be related to sensory-motor dysfunction.

Evolución de la memoria episódica en pacientes epilépticos sometidos a lobectomía temporal / Evolution of episodic memory in epileptic patients submitted to temporal lobectomy

Introducción: La memoria episódica resulta vulnerable a la lobectomía temporal. Nuestro objetivo es describir los cambios que aparecen en este subsistema de memoria, en pacientes sometidos a lobectomía temporal realizada como estrategia para control de crisis. Pacientes y Métodos: La muestra está compuesta por 11 pacientes, los cuales fueron evaluados antes de realizar la lobectomía temporal y al año de ésta, utilizando una batería de pruebas neuropsicológicas. Resultados: Observamos disminución en el rendimiento mnésico, en la modalidad ipsilateral al hemisferio donde se realiza la lobectomía y aumento en la modalidad relacionada con el hemisferio contralateral a la intervención. Sin embargo estas diferencias en elrendimiento entre los dos momentos evaluativos no se manifiestan en igual magnitud en todas las variables evaluadas ni alcanzan valor estadístico significativo. Conclusiones: Asociado a la lobectomía temporal el perfil neuropsicológico de la memoria episódica muestra disminución del rendimiento en la modalidad ipsilateral a la cirugía y mejoría en la modalidad contralateral, evolución esta que refuerza el supuesto de lateralización funcional.

Introduction: Episodic memory is vulnerable to temporal lobectomy. Our objective is to describe the changes that appear in this memory sub-system in patients submitted to temporal lobectomy, as a strategy to crisis control. Patients and methods: The simple is composed of 11 patients who were evaluated before performing the temporal lobectomy and a year after, using neuropsychologic tests.Results: We observed a diminishing in the mnesic rendering, in the ipsilateral modality to the hemisphere where the lobectomy is performed and an increase in the modality related with the contralateral hemisphere to that of the intervention. But nevertheless, these differences as to the rendering of the evaluative moments that neither manifest themselves in thesame magnitude in all evaluated variables nor reach significant statistical value. Conclusions: The neuropsychologic profile of episodic memory associated to temporal lobectomy shows a diminishing in therendering of ipsilateral modality to surgery, but an improvement in the contralateral modality an evolution that reinforces the supposing of a functional lateralization.

A neurofunctional evaluation strategy for presurgical selection of temporal lobe epilepsy patients.

Introduction Temporal lobe epilepsy (TLE) is the prototype of a surgically correctable syndrome. Successful surgical outcomes depend on a thorough presurgical evaluation aimed primarily at identifying the epileptogenic zone. Objective Describe the noninvasive presurgical selection and evaluation strategy for TLE patients introduced at the International Neurological Restoration Center (CIREN) in Havana, Cuba, and evaluated between 2001 and 2006 for its accuracy in identifying candidates for non-lesional resection surgery. Methods Ictal onset electrographic patterns of 1,679 seizures in 72 patients with drug-resistant partial epilepsy, obtained through longterm scalp Video EEG (V-EEG) monitoring, were evaluated. The correlation between the V-EEG-defined epileptogenic zone and the dysfunction shown by single photon emission computed tomography (ictal and interictal brain SPECT) and nuclear magnetic resonance spectroscopy (MRS) was established. Results V-EEG monitoring determined that 44.4% of evaluated patients had complex partial temporal lobe seizures. Identification of patients with medial temporal epilepsy (MTE) increased as a result of lateralization and localization of the dominant mean ictal pattern frequency (5.56 ± 1.31 Hz) during the period of maximum spectral power VARETA localization of an ictal epileptiform activity source coincided with the epileptogenic zone in all TLE patients who subsequently underwent a successful temporal lobectomy. Semiquantitative analysis of ictal and interictal brain SPECT images, as well as metabolic ratios measured by MRS, combined with V-EEG findings, enabled localization/lateralization of the epileptogenic zone in TLE patients whose MRIs were normal or showed bilateral structural abnormalities. Conclusions Confirmation of correct localization/lateralization of the epileptogenic zone following successful surgical outcomes in selected TLE patients led CIREN to develop a surgical treatment strategy for patients in Cuba with drug-resistant temporal lobe epilepsy. This strategy offers an appropriate, cost-effective treatment alternative for developing countries like Cuba, with the benefit of significantly improving TLE patients' quality of life.

Phase I single-dose study of intracavitary-administered Nimotuzumab labeled with 188 Re in adult recurrent high-grade glioma.

Radioimmunotherapy (RIT) may improve the management of malignant gliomas. A Phase I clinical trial was performed to evaluate, for the first time, the toxicity and clinical effect of an intracavitary administration of a single dose of Nimotuzumab (h-R3) labeled wit (188)Re. Nimotuzumab is a humanized monoclonal antibody directed against epidermal growth factor receptors. Three patients with anaplastic astrocytoma (AA) and 8 with glioblastoma multiforme (GBM) were intended to be treated with 3 mg of mAb labelled with 10 or 15 mCi of (188)Re. In patients treated with 10 mCi (n=6) transitory worsening of pre-existing neurological symptoms were observed. Two patients treated with 15 mCi (n=4) developed early severe neurological symptoms and one also developed late severe toxicity (radionecrosis). In the group treated with 10 mCi, 1 GBM patient died in progression 6 months after the treatment, 2 patients (1 GBM and 1 AA) developed stable disease during 3 months. One GBM patient had partial response for more than 1 year and 2 patients (1 GBM and 1 AA) were asymptomatic and in complete response after 3 years of treatment. Maximal tolerated dose of the radioimmunoconjugate (188)Re-Nimotuzumab was 3 mg of the h-R3 labelled with 10 mCi of (188)Re. The radioimmunoconjugate showed a high retention in the surgical created resection cavity and the brain adjacent tissues with a mean value of 85.5 % of the injected dose one hour post-administration. This radioimmunoconjugate may be relatively safe and a promising therapeutic approach for treating high grade gliomas.

Autoradiography reveals selective changes in serotonin binding in neocortex of patients with temporal lobe epilepsy.

The main goal of the present study was to evaluate binding to serotonin in the neocortex surrounding the epileptic focus of patients with mesial temporal lobe epilepsy (MTLE). Binding to 5-HT, 5-HT(1A), 5-HT(4), 5-HT(7) receptors and serotonin transporter (5-HTT) in T1-T2 gyri of 15 patients with MTLE and their correlations with clinical data, neuronal count and volume were determined. Autopsy material acquired from subjects without epilepsy (n=6) was used as control. The neocortex from MTLE patients demonstrated decreased cell count in layers III-IV (21%). No significant changes were detected on the neuronal volume. Autoradiography experiments showed the following results: reduced 5-HT and 5-HT(1A) binding in layers I-II (24% and 92%, respectively); enhanced 5-HT(4) binding in layers V-VI (32%); no significant changes in 5-HT(7) binding; reduced 5-HTT binding in all layers (I-II, 90.3%; III-IV, 90.3%, V-VI, 86.9%). Significant correlations were found between binding to 5-HT(4) and 5-HT(7) receptors and age of seizure onset, duration of epilepsy and duration of antiepileptic treatment. The present results support an impaired serotoninergic transmission in the neocortex surrounding the epileptic focus of patients with MTLE, a situation that could be involved in the initiation and propagation of seizure activity.

Aging impairs amygdala-hippocampus interactions involved in hippocampal LTP.

Aging impairs amygdala-hippocampus interactions involved in hippocampal LTP. NEUROBIOL. AGING. We have recently shown that the stimulation of the basolateral nucleus of the amygdala (BLA) is able to prolong early-LTP (<4h) into late-LTP (>4h) in the dentate gyrus. To study whether aging affects this interaction, aged (24-27 months) rats were used, classified as cognitively impaired (I), or non-impaired (N) by means of their results in the Morris water maze. Paired pulses (30-90 ms interval) showed no differences among age groups. Among young controls, the early-LTP induced in the dentate gyrus by stimulation of the perforant path (PP) was prolonged in a late-LTP when the BLA was stimulated 15 min later. In aged-impaired rats the stimulation of the PP induced a reduced LTP, decaying to baseline in less than 2 h. BLA stimulation was without effect. Aged non-impaired rats showed an early-LTP identical to that of young animals; however, stimulation of the BLA showed no effect. These results suggest that deficient synaptic plasticity and memory functions in aged animals might be caused, in part by impaired mechanisms of heterosynaptic reinforcement.

Aging impairs amygdala-hippocampus interactions involved inhippocampal LTP#6

We have recently shown that the stimulation of the basolateral nucleus of the amyddala (BLA) is able to prolong early-LTP (<4h) into late-LTP (>4h) in the dentate gyrus. To study whether aging affects this interaction, aged (24-27 months) rats were used, classified as cognitively impaired (I), or non-impaired (N) by means of their results in the Morris water maze. Paired pulses (30-90 ms interval) showed no differences among agegroups. Among young controls, the early-LTP induced in the dentate gyrus by stimulation of the perforant path (PP) was prolonged in a late-LTP when the BLA was stimulated 15 min later. In aged-impaired rats the stimulation of the PP induced a reduced LTP, decaying to baseline in less than 2 h. BLA stimulation was without effect. Aged non-impaired rats showed an early-LTP identical to that of young animals; however, stimulation of the BLA showed no effect. These results suggest that deficient synaptic plasticity and memory functions in aged animals might be caused, in part by impaired mechanisms of heterosynaptic reinforcemen(AU)

Biopsia estereotáxica de lesiones intracraneales: revisión del tema / Stereotactic biopsy in intracranial lesion: a revision of the theme

Las estrategias terapéuticas en las lesiones expansivas intracraneales son más efectivas cuando se basan en diagnósticos histopatológicas más que en hallazgos clínicos y radiológicos. El desarrollo de la neuroimagenología, la creación de softwares cada vez más versátiles y eficientes han hecho de esta técnica un procedimiento exacto y seguro para el diagnóstico de lesiones pequeñas localizadas profundamente. Objetivos. Revisar las indicaciones fundamentales de esta técnica de diagnóstico, describir la metodología general para la realización de la misma y conocer las principales complicaciones, describiendo los aspectos técnicos esenciales para evitarlas. Conclusiones. La biopsia estereotáxica en las condiciones actuales es un método de diagnóstico fácil y seguro, con un indice de complicaciones mínimos, pero el refinamiento en las indicaciones y el conocimiento metodológico de la técnica es de vital importancia para evitar resultados caastróficos en manos poco experimentadas(AU)

Resección microquirúrgica estereotáxica de tumores intracraneales guiada por imagen y asistida por computadora / Microsurgical stereotaxic resection of intracranial tumors guided by computer-assisted image

Se reporta que la orientación espacial durante la microcirugía, constituye un elemento indispensable. Se demuestra esta aplicación de la cirugía estereotáxica en el Centro Internacional de Restauración Neurológica (CIREN) de mayo de 1994 a febrero de 1998, al describir la realización de 65 intervenciones microquirúrgicas en condiciones estereotáxicas, a 62 pacientes con tumores cerebrales intracraneales. El proceder se dividió en 3 etapas: adquisición de la imagen, tomografía axial computadorizada, planificación quirúrgica, con sistema de planeamiento STASSIS y procederes microquirúrgicos, que incluyeron los sistemas estereotáxicos: Leksell, Micromar y Estereoflex. Del total, 27 de estos pacientes presentaron tumores gliales, 33 no gliales y sólo 2 lesiones no neoplásicas de localización y tamaño variados. Se realizaron 30 resecciones totales. La morbilidad quirúrgica fue mínima y no hubo mortalidad quirúrgica. Las principales ventajas del método son: localización exacta de la craneotomía, fácil orientación espacial, facilidad para distinguir los límites entre el tumor y el tejido sano. Se verificó la aplicabilidad del Estereoflex a la microcirugía cerebral (AU)

Resección microquirúrgica estereotáxica de tumores intracraneales guiada por imagen y asistida por computadora / Microsurgical stereotaxic resection of intracranial tumors guided by computer-assisted image

Se reporta que la orientación espacial durante la microcirugía, constituye un elemento indispensable. Se demuestra esta aplicación de la cirugía estereotáxica en el Centro Internacional de Restauración Neurológica (CIREN) de mayo de 1994 a febrero de 1998, al describir la realización de 65 intervenciones microquirúrgicas en condiciones estereotáxicas, a 62 pacientes con tumores cerebrales intracraneales. El proceder se dividió en 3 etapas: adquisición de la imagen, tomografía axial computadorizada, planificación quirúrgica, con sistema de planeamiento STASSIS y procederes microquirúrgicos, que incluyeron los sistemas estereotáxicos: Leksell, Micromar y Estereoflex. Del total, 27 de estos pacientes presentaron tumores gliales, 33 no gliales y sólo 2 lesiones no neoplásicas de localización y tamaño variados. Se realizaron 30 resecciones totales. La morbilidad quirúrgica fue mínima y no hubo mortalidad quirúrgica. Las principales ventajas del método son: localización exacta de la craneotomía, fácil orientación espacial, facilidad para distinguir los límites entre el tumor y el tejido sano. Se verificó la aplicabilidad del Estereoflex a la microcirugía cerebral(AU)

It is reported that spatial guidance during microsurgery is an essential element. This application of stereotaxic surgery is shown at the International Center of Neurological Restoration (CIREN, in Spanish) from May, 1994, to February, 1998, on describing the performance of 65 microsurgical procedures under stereotaxic conditions among 62 patients with cerebral intracranial tumors. The procedure was divided into 3 stages: image adquisition, CAT, surgical planning , with STASSIS planning system, and microsurgical procedures that included the Leksell, Micromar and Esteroflex stereotaxic systems. 27 of the total of patients presented glial tumors; 33, non-glial; and only 2 non-neoplastic lesions of diverse localization and size. 30 total resections were made. Surgical morbidity was minimum and there was no surgical mortality. The main advantages of this method are: exact localization of the craniotomy, easy spatial guidance, and the opportunity to distinguish the limits between the tumor and the sound tissue. The possibility to apply Esteroflex to cerebral microsurgery was demonstrated(AU)