title: Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice.
abstract: There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus, and obesity, promote cognitive impairment; however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiologic conditions. To establish a direct relationship between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH), the NO synthase inhibitor l-NG-Nitroarginine methyl ester (L-NAME), and the COX inhibitor indomethacin decreased NVC by over 60% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition), and impairment in motor coordination (Rotarod). Blood pressure (tail cuff) and basal cerebral perfusion (arterial spin labeling perfusion MRI) were unaffected. Thus, selective experimental disruption of NVC is associated with significant impairment of cognitive and sensorimotor function, recapitulating neurologic symptoms and signs observed in brain aging and pathophysiologic conditions associated with accelerated cerebromicrovascular aging.
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tarantini
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Hertelendy
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: M Noa
authors.initials: MN
authors.lastname: Valcarcel-Ares
authors.affiliation: Oklahoma Medical Research Foundation, Department of Pathology, Advanced Magnetic Resonance Center, Oklahoma City, Oklahoma, USA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Smith
authors.affiliation: Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Akos
authors.initials: A
authors.lastname: Menyhart
authors.affiliation: Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Farkas
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Hodges
authors.affiliation: Oklahoma Medical Research Foundation, Department of Pathology, Advanced Magnetic Resonance Center, Oklahoma City, Oklahoma, USA.
authors.forename: Rheal
authors.initials: R
authors.lastname: Towner
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Deak
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Neurosurgery, Szentagothai Research Center, University of Pecs, Pecs, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Neurosurgery, Szentagothai Research Center, University of Pecs, Pecs, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Neurosurgery, Szentagothai Research Center, University of Pecs, Pecs, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000523:psychology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D005684:Gait / Q000187:drug effects; D018737:Hand Strength; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D000069336:Neurovascular Coupling / Q000187:drug effects*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D004856:Postural Balance / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D052248:Nitric Oxide Synthase Type I; D000090762:Cytochrome P-450 CYP2J2; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin