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Cremers T.I.F.H.,University of Groningen | Cremers T.I.F.H.,Brains On Line BV | Cremers T.I.F.H.,Brains On line LLC | Dremencov E.,University of Groningen | And 4 more authors.
International Journal of Neuropsychopharmacology | Year: 2010

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are used as a first-line treatment in depression. However, many depressed patients are also treated with benzodiazepines to alleviate increased anxiety and sleep disturbances normally associated with depression. Since benzodiazepines inhibit 5-HT neuronal firing activity, they might attenuate SSRI-induced increase in extracellular 5-HT levels. This study aimed to assess, using in-vivo microdialysis, the effects of the benzodiazepines oxazepam or temazepan on the SSRI paroxetine-induced 5-HT increase in the hippocampus of freely moving guinea-pigs. It was found that the acute systemic administration of paroxetine increased extracellular 5-HT levels. Pre-administration of oxazepam or temazepam significantly diminished the paroxetine-induced elevation of extracellular 5-HT levels (from 350% to 200% of baseline). It was concluded that benzodiazepines attenuate the ability of SSRIs to elevate hippocampal 5-HT levels. Thus, co-administration of benzodiazepines might affect the therapeutic efficacy of SSRI treatment. © 2010 CINP.

Giorgetti M.,Medivation Inc. | Gibbons J.A.,Medivation Inc. | Bernales S.,Medivation Inc. | Alfaro I.E.,Fundacion Ciencia para la Vida | And 6 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-D-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 ± 0.43, 14 ± 5.1, and 172 ± 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (Ki = 105 ± 18 μM) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (Ki = 0.54 ± 0.05 μM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC50 > 50 μM), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.

Cordeiro C.A.,Brains On Line BV | Cordeiro C.A.,University of Groningen | de Vries M.G.,Brains On Line BV | Ngabi W.,University of Groningen | And 6 more authors.
Biosensors and Bioelectronics | Year: 2015

Enzyme-based amperometric biosensors are widely used for monitoring key biomarkers. In experimental neuroscience there is a growing interest in in vivo continuous and simultaneous monitoring of metabolism-related biomarkers, like glucose, lactate and pyruvate. The use of multiplex biosensors will provide better understanding of brain energy metabolism and its role in neuropathologies such as diabetes, ischemia, and epilepsy.We have developed and characterized an implantable multiplex microbiosensor device (MBD) for simultaneous and continuous in vivo monitoring of glucose, lactate, and pyruvate.First, we developed and characterized amperometric microbiosensors for monitoring lactate and pyruvate. In vitro evaluation allowed us to choose the most suitable biosensors for incorporation into the MBD, along with glucose and background biosensors. Fully assembled MBDs were characterized in vitro. The calculated performance parameters (LOD, LR, LRS, IMAX and appKM) showed that the multiplex MBD was highly selective and sensitive (LRS≥100nA/mM) for each analyte and within an adequate range for in vivo application.Finally, MBDs were implanted in the mPFC of anesthetized adult male Wistar rats for in vivo evaluation. Following an equilibration period, baseline brain levels of glucose (1.3±0.2. mM), lactate (1.5±0.4. mM) and pyruvate (0.3±0.1. mM) were established. Subsequently, the MBDs recorded the responses of the animals when submitted to hyperglycemic (40% glucose i.v.) and hypoglycemic (5. U/kg insulin i.v.) challenges. Afterwards, MBDs were recalibrated to convert electrochemical readings into accurate substrate concentrations and to assess biofouling. The presented MBD can monitor simultaneously multiple biomarkers in vivo. © 2014 Elsevier B.V.

Woodling N.S.,Stanford University | Woodling N.S.,University College London | Colas D.,Stanford University | Colas D.,French National Center for Scientific Research | And 19 more authors.
Brain | Year: 2016

Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers. © 2016 The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Johansson J.U.,Stanford University | Johansson J.U.,SRI International | Woodling N.S.,Stanford University | Woodling N.S.,University College London | And 9 more authors.
Journal of Clinical Investigation | Year: 2015

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/ prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.

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