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MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs.

ABSTRACT: Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies.We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs.MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated.Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 ?g/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm.The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.

SUBMITTER: Mar AC

PROVIDER: S-EPMC5591806 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs.

Mar Adam C AC Nilsson Simon R O SRO Gamallo-Lana Begoña B Lei Ming M Dourado Theda T Alsiö Johan J Saksida Lisa M LM Bussey Timothy J TJ Robbins Trevor W TW

Psychopharmacology 20170726 19

<h4>Rationale</h4>Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies.<h4>Objectives</h4>We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treat ...[more]

PMID: 28744563

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Project description:Introduction: Alzheimer's disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-β (Aβ) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown. Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aβ1-42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments. Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aβ1-42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD.

Project description:ObjectiveThe purpose was to examine Dual Task (DT) performance in patients surviving severe and critical COVID-19 compared to patients with chronic lung disease (CLD). Secondarily, we aimed to determine the psychometric properties of the Timed Up and Go (TUG) test in patients surviving COVID-19.DesignProspective, cross-sectional, observational study.SettingAcademic medical center within United States.PatientsNinety-two patients including 36 survivors of critical COVID-19 that required mechanical ventilation (critical-COVID), 20 patients recovering from COVID-19 that required supplemental oxygen with hospitalization (severe-COVID), and 36 patients with CLD serving as a control group.Measurements and main resultsPatients completed the TUG, DT-TUG, Short Physical Performance Battery (SPPB), and Six Minute Walk Test (6MWT) 1-month after hospital discharge. A subset of patients returned at 3-months and repeated testing to determine the minimal detectable change (MDC). Critical-COVID group (16.8 ± 7.3) performed the DT-TUG in significantly slower than CLD group (13.9 ± 4.8 s; P = .024) and Severe-COVID group (13.1 ± 5.1 s; P = .025). Within-subject difference between TUG and DT-TUG was also significantly worse in critical-COVID group (-21%) compared to CLD (-10%; P = .012), even despite CLD patients having a higher comorbid burden (P < .003) and older age (P < .001). TUG and DT-TUG demonstrated strong to excellent construct validity to the chair rise test, gait speed, and 6MWT for both COVID-19 groups (r = -0.84to 0.73, P < .05). One- and 3-months after hospital discharge there was a floor effect of 14% (n = 5/36) and 5.2% (n = 1/19), respectively for patients in the critical-COVID group. Ceiling effects were noted in four (11%) critical-COVID, six (30%) severe-COVID patients for the TUG and DT-TUG at 1-month.ConclusionThe ability to maintain mobility performance in the presence of a cognitive DT is grossly impaired in patients surviving critical COVID-19. DT performance may subserve the understanding of impairments related to Post-intensive care syndrome (PICS) for survivors of critical illness.

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MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs.

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MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs.

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