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Delayed atomoxetine or fluoxetine treatment coupled with limited voluntary running promotes motor recovery in mice after ischemic stroke

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Neural Regeneration Research 2021年第7期16卷 1244-1251页

作者： Faisal F.Alamri Abdullah Al Shoyaib Nausheen Syeara Anisha Paul Srinidhi Jayaraman serob t.karamyan thiruma V.Arumugam Vardan t.karamyan Department of Pharmaceutical Sciences School of PharmacyTexas Tech University Health Sciences CenterAmarilloTXUSA Department of Pharmacology Faculty of PharmacyYerevan State Medical UniversityYerevanArmenia Department of Physiology Anatomy and MicrobiologySchool of Life SciencesLa Trobe UniversityMelbourneAustralia Center for Blood Brain Barrier Research School of PharmacyTexas Tech University Health Sciences CenterAmarilloTXUSA College of Sciences and Health Profession King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research CenterJeddahSaudi Arabia

Currently, there is an unmet need for treatments promoting post-stroke functional *** aim of this study was to evaluate and compare the dose-dependent effect of delayed atomoxetine or fluoxetine therapy(starting on post-stroke day 5), coupled with limited physical exercise(2 hours daily voluntary wheel running;post-stroke days 9 to 42), on motor recovery of adult male mice after photothrombotic *** drugs are selective norepinephrine or serotonin reuptake inhibitors indicated for disorders unrelated to *** predetermined primary end-point for this study was motor function measured in two tasks of spontaneous motor behaviors in grid-walking and cylinder ***, we quantified the running distance and speed throughout the study, the number of parvalbumin-positive neurons in the medial agranular cortex and infarct *** sensorimotor tests revealed that neither limited physical exercise nor a drug treatment alone significantly facilitated motor recovery in mice after ***, combination of physical exercise with either of the drugs promoted restoration of motor function by day 42 post-stroke, with atomoxetine being a more potent *** was accompanied by a significant decrease in parvalbumin-positive inhibitory interneurons in the ipsilateral medial agranular cortex of mice with recovering motor function, while infarct volumes were comparable among experimental *** further validated in larger studies, our observations suggest that add-on atomoxetine or fluoxetine therapy coupled with limited, structured physical rehabilitation could offer therapeutic modality for stroke survivors who have difficulty to engage in early, high-intensity ***, in light of the recently completed Assessment o F Fluoxet INe In s troke recover Y(AFFINItY) and Efficacy o F Fluoxetine-a randomis Ed Controlled trial in Stroke(EFFECtS) trials, our observations call for newly designed studies where fluoxetine or atomoxeti

关键词： drug repurposing neural repair physical exercise physiotherapy post-stroke recovery pre-clinical trial FLAME trial selective norepinephrine reuptake inhibitor selective serotonin reuptake inhibitor stroke pharmacotherapy

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the role of peptidase neurolysin in neuroprotection and neural repair after stroke

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Neural Regeneration Research 2021年第1期16卷 21-25页

作者： Vardan t.karamyan Department of Pharmaceutical Sciences and Center for Blood Brain Barrier Research School of PharmacyTTUHSCAmarilloTXUSA

Current experimental stroke research has evolved to focus on detailed understanding of the brain’s self-protective and restorative mechanisms,and harness this knowledge for development of new *** this context,the role of peptidases and neuropeptides is of growing *** this focused review,peptidase neurolysin(Nln)and its extracellular peptide substrates are briefly discussed in relation to pathophysiology of ischemic *** of Nln following stroke is viewed as a compensatory cerebroprotective mechanism in the acute phase of stroke,because the main neuropeptides inactivated by Nln are neuro/cerebrotoxic(bradykinin,substance P,neurotensin,angiotensin II,hemopressin),whereas the peptides generated by Nln are neuro/cerebroprotective(angiotensin-(1–7),Leu-/Met-enkephalins).this notion is confirmed by experimental studies documenting aggravation of stroke outcomes in mice after inhibition of Nln following stroke,and dramatic improvement of stroke outcomes in mice overexpressing Nln in the *** role of Nln in the(sub)chronic phase of stroke is less clear and it is likely,that this peptidase does not have a major role in neural repair *** is because,the substrates of Nln are less uniform in modulating neurorestorative mechanisms in one direction,some appearing to have neural repair enhancing/stimulating potential,whereas others doing the *** studies focusing on the role of Nln in pathophysiology of stroke should determine its potential as a cerebroprotective target for stroke therapy,because its unique ability to modulate multiple neuropeptide systems critically involved in brain injury mechanisms is likely advantageous over modulation of one pathogenic pathway for stroke pharmacotherapy.

关键词： compensatory cerebroprotection drug target endogenous neuroprotective mechanism neuropeptide neurorestoration peptidase

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