Pharmacologically-Induced Neurovascular Uncoupling is Associated with Cognitive Impairment in Mice

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 thi...

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Published in:Journal of cerebral blood flow and metabolism 2015-11, Vol.35 (11), p.1871-1881
Main Authors: Tarantini, Stefano, Hertelendy, Peter, Tucsek, Zsuzsanna, Valcarcel-Ares, M Noa, Smith, Nataliya, Menyhart, Akos, Farkas, Eszter, Hodges, Erik L, Towner, Rheal, Deak, Ferenc, Sonntag, William E, Csiszar, Anna, Ungvari, Zoltan, Toth, Peter
Format: Article
Language:English
Subjects:
Animals
Blood Pressure - drug effects
Cerebrovascular Circulation - drug effects
Cognition Disorders - chemically induced
Cognition Disorders - psychology
Cyclooxygenase Inhibitors - pharmacology
Cytochrome P-450 Enzyme System - drug effects
Enzyme Inhibitors - pharmacology
Evoked Potentials, Somatosensory - drug effects
Gait - drug effects
Hand Strength
Indomethacin - pharmacology
Male
Maze Learning - drug effects
Memory - drug effects
Mice
Mice, Inbred C57BL
Neurovascular Coupling - drug effects
NG-Nitroarginine Methyl Ester - pharmacology
Nitric Oxide Synthase Type I - antagonists & inhibitors
Original
Postural Balance - drug effects
Recognition (Psychology) - drug effects
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Summary: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.
ISSN:0271-678X
1559-7016
DOI:10.1038/jcbfm.2015.162