Safety and efficacy of transcranial direct current stimulation in acute experimental ischemic stroke.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation is emerging as a promising tool for the treatment of several neurological conditions, including cerebral ischemia. The therapeutic role of this noninvasive treatment is, however, limited to chronic phases of stroke. We thus ought to investigate whether different stimulation protocols could also be beneficial in the acute phase of experimental brain ischemia. METHODS: The influence of both cathodal and anodal transcranial direct current stimulation in modifying brain metabolism of healthy mice was first tested by nuclear magnetic resonance spectroscopy. Then, mice undergoing transient proximal middle cerebral artery occlusion were randomized and treated acutely with anodal, cathodal, or sham transcranial direct current stimulation. Brain metabolism, functional outcomes, and ischemic lesion volume, as well as the inflammatory reaction and blood brain barrier functionality, were analyzed. RESULTS: Cathodal stimulation was able, if applied in the acute phase of stroke, to preserve cortical neurons from the ischemic damage, to reduce inflammation, and to promote a better clinical recovery compared with sham and anodal treatments. This finding was attributable to the significant decrease of cortical glutamate, as indicated by nuclear magnetic resonance spectroscopy. Conversely, anodal stimulation induced an increase in the postischemic lesion volume and augmented blood brain barrier derangement. CONCLUSIONS: Our data indicate that transcranial direct current stimulation exerts a measurable neuroprotective effect in the acute phase of stroke. However, its timing and polarity should be carefully identified on the base of the pathophysiological context to avoid potential harmful side effects.

Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity.

The functional significance of adult neural stem and progenitor cells in hippocampal-dependent learning and memory has been well documented. Although adult neural stem and progenitor cells in the subventricular zone are known to migrate to, maintain and reorganize the olfactory bulb, it is less clear whether they are functionally required for other processes. Using a conditional transgenic mouse model, selective ablation of adult neural stem and progenitor cells in the subventricular zone induced a dramatic increase in morbidity and mortality of central nervous system disorders characterized by excitotoxicity-induced cell death accompanied by reactive inflammation, such as 4-aminopyridine-induced epilepsy and ischaemic stroke. To test the role of subventricular zone adult neural stem and progenitor cells in protecting central nervous system tissue from glutamatergic excitotoxicity, neurophysiological recordings of spontaneous excitatory postsynaptic currents from single medium spiny striatal neurons were measured on acute brain slices. Indeed, lipopolysaccharide-stimulated, but not unstimulated, subventricular zone adult neural stem and progenitor cells reverted the increased frequency and duration of spontaneous excitatory postsynaptic currents by secreting the endocannabinod arachidonoyl ethanolamide, a molecule that regulates glutamatergic tone through type 1 cannabinoid receptor (CB(1)) binding. In vivo restoration of cannabinoid levels, either by administration of the type 1 cannabinoid receptor agonist HU210 or the inhibitor of the principal catabolic enzyme fatty acid amide hydrolase, URB597, completely reverted the increased morbidity and mortality of adult neural stem and progenitor cell-ablated mice suffering from epilepsy and ischaemic stroke. Our results provide the first evidence that adult neural stem and progenitor cells located within the subventricular zone exert an 'innate' homeostatic regulatory role by protecting striatal neurons from glutamate-mediated excitotoxicity.

[Expression of epidermal growth factor receptor in renal biopsy from patients with adolescent nephronophthisis]. / Expresión del receptor del factor de crecimiento epidérmico en biopsias renales de pacientes con nefronoptisis del adolescente.

INTRODUCTION: In Venezuela has been described a new form of nephronophthisis, called adolescent nephronophthisis, with clinical and histological findings very similar to others varieties described. However, pathogenesis in not well known. The aim of this study was to determine the expression of human epidermal growth factor receptor (EGFR) in tubular epithelial cells of patients with adolescent nephronophthisis. METHODS: Renal biopsies of 8 patients with adolescent nephronophthisis were studied by immunohistochemistry to determine renal expression of EGFR. RESULTS: In all patients, there was no expression of epidermal growth factor receptor. CONCLUSION: These findings indicate a deficiency of growth factor receptor in undifferentiated epithelial cells, which could be one factor in the development of cysts in nephronophthisis.

Frequency of abnormal correlation between leptin and the body mass index during first and second generation antipsychotic drug treatment.

BACKGROUND: Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine. METHODS: This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229). RESULTS: None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration. CONCLUSIONS: Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures.

Similar frequency of abnormal correlation between serum leptin levels and BMI before and after olanzapine treatment in schizophrenia.

Melkersson proposed leptin dysregulation as a factor in the olanzapine-induced metabolic dysfunction. Their suggestion was based on the absence of the expected positive correlation between serum leptin levels and the BMI, and the loss of the sex-dependent difference in leptin levels, which are higher in women. Although subsequent studies did not confirm that proposal, few of them assessed basal leptin levels and corrected for body fat percentage. Along with these variables, we added a precise definition of participants out of the expected positive correlation in a large sample of schizophrenia patients. Sixty patients (26 women and 34 men) with severe schizophrenia undergoing chronic hospitalization and conventional antipsychotic treatment were switched to olanzapine (10-20 mg/day). We assessed at baseline, and at weeks 8 and 16 of treatment, the percentage of participants with abnormal correlation (out of the 95% confidence interval in the regression line) between leptin levels and the BMI, and the correlation between leptin and insulin, glucose, the insulin resistance index, c-reactive protein (CRP) and treatment response. Leptin levels were higher in women than in men (P<0.01). The positive correlation between leptin levels, BMI and percentage of fat were preserved. After olanzapine, 3.8% of women and 2.9-5.8% of men were out the 95% confidence interval, and the proportion was similar at baseline. Glucose, insulin, the insulin resistance index and the CRP levels significantly increased after olanzapine. The impact of olanzapine on leptin regulation appears discrete and limited to a small number of participants. Additional studies must clarify the features that render them to metabolic dysregulation.

[Protective effect of melatonin and sodium thiosulphate on histopathology and ultrastructure of the kidney in rats with acute paraquat poisoning]. / Efecto protector de la melatonina y el tiosulfato de sodio sobre la histopatología y la ultraestructura del riñon en ratas con intoxicación aguda por Paraquat.

Paraquat (PQ) toxicity produces severe injures in many major organs systems, including kidney, developing renal failure with fatal evolution in most of the cases. Several antidotes have been used in the treatment of paraquat intoxication without satisfactory results. The antioxidative effect of melatonin (MLT) and sodium thiosulphate (STS) on kidney in rats with acute intoxication by PQ was studied. Forty male Wistar rats were used, divided in 4 groups of 10 rats each. Group I, control, was injected intraperitoneally (ip) with 1 ml of saline solution; group II, received DL50 of PQ, ip; groups III and IV, DL50 of PQ, and simultaneously the first dose of MLT (15 mg/kg, ip) or STS (1,5 g/kg, i.p.) respectively. Thirty minutes later, groups III and IV received a second similar dose of MLT and TSS. After 24 hours, rats were sacrificed with pentobarbital, and kidneys were extracted for morphological study. Light and electronic microscopy observations showed in group II morphological changes of acute tubular necrosis in proximal tubule in group II, similar findings, with lesser magnitude, were observed in the animals treated with the antidotes, suggesting a partial protection. In conclusion, individual use of MLT and STS at the doses and time used partially prevent damage caused by paraquat to the cell. In consequence, more experiments with these drugs are necessary to considere them as specific treatments in cases of poisoning by paraquat.

Efecto protector de la melatonina y el tiosulfato de sodio sobre la histopatología y la ultraestructura del riñón en ratas con intoxicación aguda por paraquat / Protective effect of melatonin and sodium thiosulphate on histopathology and ultrastructure of the kidney in rats with acute intoxication for paraquat

La intoxicación aguda con paraquat (PQ) produce daños severos en muchos órganos, entre ellos el riñón, donde se desarrolla insuficiencia renal. Se han utilizado varios antídotos en el tratamiento de la intoxicación por PQ sin resultados satisfactorios. En este estudio se determinó el efecto protector de la melatonina (MLT) y el tiosulfato de sodio (TSS) sobre el riñón, en ratas con intoxicación aguda por paraquat. Se utilizaron 40 ratas Wistar, machos, divididas en 4 grupos de 10 ratas cada uno. Al grupo I, control, se le inyectó 1 ml de solución fisiológica, vía intraperitoneal (ip); el grupo II, recibió DL50 de PQ, ip; los grupos III y IV recibieron DL50 de PQ, y simultáneamente la primera dosis de MLT (15 mg/kg) o TSS (1,5 g/kg), respectivamente (ip). Treinta minutos después, los grupos III y IV recibieron otra dosis igual de MLT y TSS. A las 24 horas de tratadas las ratas fueron sacrificadas con pentobarbital, extrayéndose el riñon para su estudio morfológico. Con la microscopía de luz y electrónica, en el grupo II se evidenciaron cambios morfológicos de necrosis tubular aguda en el túbulo proximal; observándose hallazgos similares de menor intensidad en los animales tratados con los antídotos, sugiriendo una protección parcial. En conclusión, el uso individual de la MLT y TSS, en las dosis y plazo empleados, revierte parcialmente el daño que causa el paraquat a la célula. En consecuencia, son necesarias más evaluaciones de estas drogas para su uso clínico en el tratamiento de la intoxicación por paraquat.

Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial.

OBJECTIVE: To assess whether metformin prevents body weight gain (BWG) and metabolic dysfunction in patients with schizophrenia who are treated with olanzapine. METHOD: Forty patients taking olanzapine (10 mg daily) were randomly allocated to a metformin (n = 20; 850 to 1700 mg daily) or placebo (n = 20) group in a 14-week double-blind study. Waist circumference (WC), BWG, body mass index (BMI) fasting glucose, insulin, and lipids were evaluated at baseline and at Weeks 7 and 14 of treatment. RESULTS: At Week 14, BWG (kg) was similar in the metformin group (5.5 kg) and the placebo group (6.3 kg), P = 0.4. There were no differences between the changes in BMI, WC, glucose, insulin, insulin resistance index (HOMA-IR), and plasma lipid levels observed in the treatment group and the placebo group; however, glucose levels decreased significantly after metformin administration (P = 0.02). The HOMA-IR decreased significantly in both groups, but 3 subjects from the placebo group developed fasting glucose levels greater than 5 mmol/L. After taking metformin, triglyceride levels increased, but the cholesterol profile improved significantly. CONCLUSIONS: Metformin did not prevent olanzapine-induced BWG. While some lipid parameters worsened during placebo, the HOMA-IR improved in both the placebo and the metformin groups. Carbohydrate metabolism impairment was not systematically observed during short-term olanzapine administration.

Propofol suppresses the sleep state-dependent P13 midlatency auditory evoked potential in the rat.

Propofol (2,6-diisopropylphenol) is a widely used anesthetic agent, but its mechanisms of action are poorly understood. In this report, the effects of three dose levels of propofol (5, 7.5, and 10mg/kg) on the amplitude of the vertex-recorded, sleep state-dependent P13 midlatency evoked potential were investigated. The P13 potential is generated, at least in part, by the ascending cholinergic reticular activating system (RAS). The RAS is known to be affected by anesthetic agents. Intravenous injections of propofol were found to reduce the amplitude of the P13 potential in a dose- and time-dependent manner. At 2min post-injection, the mean P13 amplitude was suppressed to 40% of its pre-injection level by the lowest dose, but was suppressed to 10% of pre-injection levels by the two higher doses of propofol. The duration of the suppression of mean P13 potential amplitude was also dose-dependent such that complete recovery occurred by 5min using 5mg/kg, by 15min using 7.5mg/kg and by 30min using 10mg/kg of propofol. Using a paired stimulus paradigm, transient effects on habituation of the P13 potential were observed but only after the highest dose. Thus, one of the mechanisms of propofol may be to affect portions of the RAS which modulate the level of arousal. It may only transiently affect higher systems known to modulate the degree of habituation of responses by the RAS (i.e. processes which modulate habituation and may participate in sensory gating and distractibility).

Effects of rotation on the P13 mid-latency auditory evoked potential in rat.

The P13 mid-latency auditory evoked potential in Rat is a sleep state-dependent response thought to be equivalent to the human P50 potential, a measure of the output of the reticular activating system. The amplitude of these potentials can be considered a measure of level of arousal, while, using a paired stimulus paradigm, the degree of habituation of the responses also can be assessed. Different durations of rotation were found to reduce the amplitude of the P13 potential, which recovered in a duration-dependent manner. Different durations of rotation led to decreases in habituation of the P13 potential again in a duration-dependent manner. These results suggest that rotation may affect the level of arousal as well as habituation to repetitive sensory inputs. Such effects could be interpreted to imply the presence, following rotation of sufficient duration, of a deficit in sensory gating, or distractibility, and are relevant for the study of the effects of space motion sickness.