Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice

Stefano Tarantini; Andriy Yabluchanksiy; Gábor A. Fülöp; Peter Hertelendy; M. Noa Valcarcel-Ares; Tamas Kiss; Jonathan M. Bagwell; Daniel O’Connor; Eszter Farkas; Farzaneh Sorond; Anna Csiszar; Zoltan Ungvari

doi:10.1007/s11357-017-0003-x

Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice

Stefano Tarantini, Andriy Yabluchanksiy, Gábor A. Fülöp, Peter Hertelendy, M. Noa Valcarcel-Ares, Tamas Kiss, Jonathan M. Bagwell, Daniel O’Connor, Eszter Farkas, Farzaneh Sorond, Anna Csiszar, Zoltan Ungvari^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-and-effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.

Original language	English (US)
Pages (from-to)	601-614
Number of pages	14
Journal	GeroScience
Volume	39
Issue number	5-6
DOIs	https://doi.org/10.1007/s11357-017-0003-x
State	Published - Dec 1 2017

Funding

The authors acknowledge that this work was supported by grants from the American Heart Association (ST, ZU and AC), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Center for Complementary and Alternative Medicine (R01-AT006526 to ZU), the National Institute on Aging (R01-AG055395, R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782, R01-NS056218), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (U54GM104938, to AY), the Presbyterian Health Foundation (to ZU, AC, AY), the EU-funded Hungarian grant EFOP-3.6.1-16-2016-00008, and from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363). All the performed procedures were approved by the Institutional Animal Care and Use Committee of the University of Oklahoma Health Sciences Center.

Keywords

Catwalk
Gait
Neurovascular coupling
Neurovascular uncoupling

ASJC Scopus subject areas

Geriatrics and Gerontology
Cardiology and Cardiovascular Medicine
Aging
Complementary and alternative medicine
veterinary (miscalleneous)

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title = "Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice",

abstract = "There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-and-effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.",

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AU - Hertelendy, Peter

AU - Valcarcel-Ares, M. Noa

AU - Kiss, Tamas

AU - Bagwell, Jonathan M.

AU - O’Connor, Daniel

AU - Farkas, Eszter

AU - Sorond, Farzaneh

AU - Csiszar, Anna

AU - Ungvari, Zoltan

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AB - There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-and-effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.

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Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice

Abstract

Funding

Keywords

ASJC Scopus subject areas

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