title: NOS knockout or inhibition but not disrupting PSD-95-NOS interaction protect against ischemic brain damage.
abstract: Promising results have been reported in preclinical stroke target validation for pharmacological principles that disrupt the N-methyl-D-aspartate receptor-post-synaptic density protein-95-neuronal nitric oxide synthase complex. However, post-synaptic density protein-95 is also coupled to potentially neuroprotective mechanisms. As post-synaptic density protein-95 inhibitors may interfere with potentially neuroprotective mechanisms and sufficient validation has often been an issue in translating basic stroke research, we wanted to close that gap by comparing post-synaptic density protein-95 inhibitors with NOS1(-/-) mice and a NOS inhibitor. We confirm the deleterious role of NOS1 in stroke both in vivo and in vitro, but find three pharmacological post-synaptic density protein-95 inhibitors to be therapeutically ineffective.
authors.affiliation: Department of Neurology, University Hospital Würzburg, Würzburg, Germany Department of Neurology, University Hospital Essen, Essen, Germany christoph.kleinschnitz@uk-essen.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: Department of Neurology, University Hospital Würzburg, Würzburg, Germany Department of Neurology, University Hospital Essen, Essen, Germany.
authors.forename: Stine
authors.initials: S
authors.lastname: Mencl
authors.affiliation: Department for Pharmacology and Personalised Medicine, CARIM, Faculty of Health, Medicine & Life Science, Maastricht University, Maastricht, The Netherlands.
authors.forename: Pamela W M
authors.initials: PWM
authors.lastname: Kleikers
authors.affiliation: Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.affiliation: Department for Pharmacology and Personalised Medicine, CARIM, Faculty of Health, Medicine & Life Science, Maastricht University, Maastricht, The Netherlands Departamento de Farmacologia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Casas
authors.affiliation: Department of Medical Informatics, Informatics Institute, Middle East Technical University, Ankara, Turkey.
authors.forename: Bilge
authors.initials: B
authors.lastname: Sürün
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Department for Pharmacology and Personalised Medicine, CARIM, Faculty of Health, Medicine & Life Science, Maastricht University, Maastricht, The Netherlands.
authors.forename: Harald H H W
authors.initials: HHHW
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000517:prevention & control*; D002545:Brain Ischemia / Q000517:prevention & control*; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051528:Guanylate Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D051528:Guanylate Kinases
keywords: Nitric oxide; excitotoxicity; experimental; free radicals; stroke