Potentiation of antiseizure and neuroprotective efficacy of standard nerve agent treatment by addition of tariquidar

Organophosphate (OP) induced seizures are commonly treated with anticholinergics, oximes and anticonvulsants. Inhibition of P-glycoprotein (PgP) has been shown to enhance the efficacy of nerve agent treatment in soman exposed rats. In the present study, the promising effects of the PgP inhibitor tariquidar were investigated in more detail in rats s.c. exposed to 150 μg/kg soman. Treatment with HI-6 and atropine sulfate (125 and 3 mg/kg i.m respectively) was administered 1 min after exposure. Diazepam (0.5 mg/kg i.m.) and/or tariquidar (7.5 mg/kg i.v.) were included either at 1 min or 40 min following onset of seizures. Animals that received tariquidar, in addition to HI-6 and atropine, at 1 min, displayed a rapid normalization of EEG activity and cessation of seizure-associated behaviour. This improvement by addition of tariquidar was even more substantial in animals that also received diazepam, either immediately or delayed. Animals exhibiting lower intensity seizures displayed less severe neuropathology (neuronal loss, microglia activation and astrogliosis), primarily in the piriform cortex, and to a lesser extent amygdala and entorhinal cortex. The present findings suggest that the interaction of tariquidar with atropine may be the decisive factor for enhanced treatment efficacy, given that atropine was previously found to be a PgP substrate. A more thorough understanding of the interactions of nerve agent antidotes, in particular the actions of central anticholinergics with benzodiazepines, could contribute to a future optimization of treatment combinations, particularly those aimed at later stage medical interventions

The age-related slow increase in amyloid pathology in APP.V717I mice activates microglia, but does not alter hippocampal neurogenesis

In Alzheimer's disease, the hippocampus is characterized by abundant deposition of amyloid peptides (amyloid β [Aβ]) and neuroinflammation. Adult hippocampal neurogenesis (AHN) is a form of plasticity that contributes to cognition and can be influenced by either or both pathology and neuroinflammation. Their interaction has been studied before in rapidly progressing transgenic mouse models with strong overexpression of amyloid precursor protein (APP) and/or presenilin 1. So far, changes in AHN and neuroinflammation remain poorly characterized in slower progressing models at advanced age, which approach more closely sporadic Alzheimer's disease. Here, we analyzed 10- to 26-month-old APP.V717I mice for possible correlations between Aβ pathology, microglia, and AHN. The age-related increase in amyloid pathology was closely paralleled by microglial CD68 upregulation, which was largely absent in age-matched wild-type littermates. Notably, aging reduced the AHN marker doublecortin, but not calretinin, to a similar extent in wild-type and APP.V717I mice between 10 and 26 months. This demonstrates that AHN is influenced by advanced age in the APP.V717I mouse model, but not by Aβ and microglial activation

Патопсихологические особенности и закономерности развития органических психических расстройств при болезни Паркинсона

Проанализированы особенности эмоционально−потребностной сферы, выраженность личностных особенностей, типы отношения к болезни у пациентов с болезнью Паркинсона (БП) и психическими расстройствами. Выявлены патопсихологические факторы формирования органического депрессивного расстройства (F06.36), органического тревожного расстройства (F06.4), органического эмоционально−лабильного расстройства (F06.6), описаны механизмы их патогенеза. Относительно деменции (F02.3) у больных БП единого патопсихологического механизма ее формирования не обнаружено, основная роль в ее патогенезе принадлежит органическому поражению головного мозга.Проаналізовано особливості емоційно−потребової сфери, виразність особистісних особливостей, типи ставлення до хвороби у пацієнтів із хворобою Паркінсона (ХП) та психічними розладами. Виявлено патопсихологічні фактори формування органічного депресивного розладу (F06.36), органічного тривожного розладу (F06.4), органічного емоційно−лабільного розладу (F06.6), описано механізми їх патогенезу. Щодо деменції (F02.3) у хворих на ХП єдиного патопсихологічного механізму її формування не виявлено, основна роль в її патогенезі належить органічному ураженню головного мозку.The peculiarities of emotion−need sphere, degree of personality peculiarities, types of attitude to the disease were analyzed in patients with Parkinson's disease (PD) and mental disorders. Pathopsychological factors of forming organic depressive disorder (F06.36), organic anxiety disorder (F06.4), organic emotional−labile disorder (F06.6) were revealed. The mechanisms of their pathogenesis were described. As for dementia (F02.3), uniform pathopsychological mechanism of its formation was not revealed in patients with PD. Main role in its pathogenesis is played by organic brain lesions

Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats

The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population

Effects of early-life stress on cognitive function and hippocampal structure in female rodents

We tested the effect of early life stress (ELS) - 24 h maternal deprivation at postnatal day 3 - on cognitive performance and hippocampal structure in 12-17 weeks old female rats. Behavioral performance was examined in: the elevated plus maze, as an index for general anxiety; the rodent Iowa gambling test, probing reward-based decision making; and the object recognition and object-in-location task, to assess non-stressful contextual memory performance. We further determined hippocampal dentate gyrus volume and cell density as well as adult proliferation and neurogenesis rates. Half of the rats was treated with the glucocorticoid receptor antagonist mifepristone during a critical pre-pubertal developmental window (postnatal days 26-28), in an attempt to ameliorate the potentially adverse behavioral consequences of ELS. Neither maternal deprivation nor treatment with the glucocorticoid antagonist affected behavioral performance of the females in any of the tasks. Also, dentate gyrus structure, proliferation and neurogenesis were not different between the groups. The lack of structural differences and a behavioral phenotype in non-stressful hippocampus dependent learning tasks fits with the lack of phenotype generally reported after ELS in female but less so in male rodents. As evident from an extensive literature review, female and male animals appear to respond more similarly to early life adversity when tested in anxiety-related tasks. This agrees with recent findings in humans suggesting that females may be relatively resilient to the structural / hippocampal effects of childhood maltreatment, but not to the anxiety and mood-related psychopathology for which childhood maltreatment is considered a risk factor