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Barcelona, Spain

There is a convincing body of evidence that oxidative stress is involved in the pathogenesis of acute pancreatitis. The effects of different radical scavengers suggested that reactive oxygen metabolites are generated at very early stage of disease and contribute to amplify the pancreatic damage. Oxidative stress is also involved in the progression of the disease from a local damage to a systemic organ failure. However, therapeutic use of antioxidants failed to clearly show a clinical benefit in different trials. Therefore, although antioxidants alone seem to be not enough for the treatment of severe acute pancreatitis, future combined therapeutic strategies should include antioxidants in its composition. © 2013 Informa UK, Ltd. Source

Amaro S.,Institute Investigacions Biomedicas August Pi i Sunyer IDIBAPS | Urra X.,Institute Investigacions Biomedicas August Pi i Sunyer IDIBAPS | Gomez-Choco M.,Institute Investigacions Biomedicas August Pi i Sunyer IDIBAPS | Obach V.,Institute Investigacions Biomedicas August Pi i Sunyer IDIBAPS | And 6 more authors.

Background and Purpose: Uric acid (UA) is a neuroprotective antioxidant that improves the benefits of alteplase in experimental ischemia. However, it is unknown whether endogenous UA also influences the response to thrombolysis in patients with stroke. Methods-A total of 317 consecutive patients treated with thrombolysis were included in a prospective stroke registry. Demographics, laboratory data, neurological course, and infarction volume were prospectively collected. Excellent outcome was defined as achieving a modified Rankin Scale score <2 at 90 days. Binary and ordinal logistic regression models were used to analyze modified Rankin Scale score at 90 days. Results-UA levels were significantly higher in patients with an excellent outcome than in patients with a poor outcome (5.82 [1.39] versus 5.42 [1.81], P=0.029). In multivariate models, increased UA levels (OR, 1.23; 95% CI, 1.03 to 1.49; P=0.025) were associated with an excellent outcome and with an increased risk of shifting to a better category across the modified Rankin Scale (OR, 1.19; 95% CI, 1.04 to 1.38; P=0.014) independently of the effect of confounders. The levels of UA and the volume of final infarction were inversely correlated (r=-0.216, P<0.001) and the inverse correlation remained after adjustment for age, sex, and baseline National Institutes of Health Stroke Scale score (t value=-2.54, P=0.01). Significantly lower UA levels were found in patients with malignant middle cerebral artery infarction and parenchymal hemorrhage postthrombolysis. Conclusions: Increased UA serum levels are associated with better outcome in patients with stroke treated with reperfusion therapies. These results support the assessment of the potential neuroprotective role of the exogenous administration of UA in patients with stroke treated with thrombolysis. © 2010 American Heart Association, Inc. Source

Current antidepressants, which inhibit the serotonin transporter (SERT), display limited efficacy and slow onset of action. Here, we show that partial reduction of SERT expression by small interference RNA (SERT-siRNA) decreased immobility in the tail suspension test, displaying an antidepressant potential. Moreover, short-term SERT-siRNA treatment modified mouse brain variables considered to be key markers of antidepressant action: reduced expression and function of 5-HT(1A)-autoreceptors, elevated extracellular serotonin in forebrain and increased neurogenesis and expression of plasticity-related genes (BDNF, VEGF, Arc) in hippocampus. Remarkably, these effects occurred much earlier and were of greater magnitude than those evoked by long-term fluoxetine treatment. These findings highlight the critical role of SERT in serotonergic function and show that the reduction of SERT expression regulates serotonergic neurotransmission more potently than pharmacological blockade of SERT. The use of siRNA-targeting genes in serotonin neurons (SERT, 5-HT(1A)-autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants. Source

Santana N.,IIBB CSIC | Santana N.,Research Center Biomedica En Red Of Salud Mental Cibersam | Mengod G.,IIBB CSIC | Mengod G.,CIBER ISCIII | And 2 more authors.
International Journal of Neuropsychopharmacology

The prefrontal cortex (PFC) is involved in behavioural control and cognitive processes that are altered in schizophrenia. The brainstem monoaminergic systems control PFC function, yet the cells/networks involved are not fully known. Serotonin (5-HT) and norepinephrine (NE) increase PFC neuronal activity through the activation of α1-adrenergic receptors (α1ARs) and 5-HT2A receptors (5-HT2ARs), respectively. Neurochemical and behavioural interactions between these receptors have been reported. Further, classical and atypical antipsychotic drugs share nm in vitro affinity for α1ARs while having preferential affinity for D2 and 5-HT2ARs, respectively. Using double in situ hybridization we examined the cellular expression of α1ARs in pyramidal (vGluT1-positive) and GABAergic (GAD65/67-positive) neurons in rat PFC and their co-localization with 5-HT2ARs. α1ARs are expressed by a high proportion of pyramidal (59-85%) and GABAergic (52-79%) neurons. The expression in pyramidal neurons exhibited a dorsoventral gradient, with a lower percentage of α1AR-positive neurons in infralimbic cortex compared to anterior cingulate and prelimbic cortex. The expression of α1A, α1B and α1D adrenergic receptors was segregated in different layers and subdivisions. In all them there is a high co-expression with 5-HT2ARs (∼80%). These observations indicate that NE controls the activity of most PFC pyramidal neurons via α1ARs, either directly or indirectly, via GABAergic interneurons. Antipsychotic drugs can thus modulate the activity of PFC via α1AR blockade. The high co-expression with 5-HT2ARs indicates a convergence of excitatory serotonergic and noradrenergic inputs onto the same neuronal populations. Moreover, atypical antipsychotics may exert a more powerful control of PFC function through the simultaneous blockade of α1ARs and 5-HT2ARs. © 2012 CINP. Source

Barbero-Camps E.,IIBB CSIC | Barbero-Camps E.,CIBER ISCIII | Fernandez A.,IIBB CSIC | Fernandez A.,CIBER ISCIII | And 7 more authors.
Human Molecular Genetics

Current evidence indicates that excess brain cholesterol regulates amyloid-b (Ab) deposition, which in turn can regulate cholesterol homeostasis.Moreover, Ab neurotoxicity is potentiated, in part, by mitochondrial glutathione (mGSH) depletion. To better understand the relationship between alterations in cholesterol homeostasis and Alzheimer's disease (AD),wegenerated a triple transgenicmice featuring sterol regulatory element-binding protein-2 (SREBP-2) overexpression in combination withAPPswe/PS1δE9 mutations (APP/PS1) to examine key biochemical and functional characteristics of AD. UnlikeAPP/PS1 mice, APP/PS1/SREBP-2 mice exhibited early mitochondrial cholesterol loading and mGSHdepletion. Moreover,β-secretase activationandAbaccumulation, correlating with oxidative damage and neuroinflammation, were accelerated in APP/PS1/SREBP-2 mice compared with APP/PS1mice. Triple transgenicmicedisplayed increasedsynaptotoxicity reflectedbyloss ofsynaptophysin and neuronal death, resulting in early object-recognition memory impairment associated with deficits in spatial memory. Interestingly, tau pathologywaspresent inAPP/PS1/SREBP-2 mice, manifested by increased tau hyperphosphorylation and cleavage, activation of tau kinases and neurofibrillary tangle (NFT) formation without expression of mutated tau. Importantly, in vivo treatment with the cell permeable GSH ethyl ester, which restored mGSH levels in APP/PS1/SREBP-2 mice, partially prevented the activation of tau kinases, reduced abnormal tau aggregation and Ab deposition, resulting in attenuated synaptic degeneration. Taken together, these results show that cholesterol-mediated mGSH depletion is a key event in AD progression, accelerating the onset of key neuropathological hallmarks of the disease. Thus, therapeutic approaches to recover mGSH may represent a relevant strategy in the treatment of AD. © The Author 2013. Published by Oxford University Press. All rights reserved. Source

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