Research Paper|Volume 17, Issue 2|pp 448—463

Chronic β3 adrenergic agonist treatment improves neurovascular coupling responses, attenuates blood-brain barrier leakage and neuroinflammation, and enhances cognition in aged mice

Duraipandy Natarajan^1,^2,³, Shoba Ekambaram³, Stefano Tarantini^1,^2,^3,⁵, Raghavendra Y. Nagaraja^1,², Andriy Yabluchanskiy^1,^2,^3,⁵, Andria F. Hedrick⁶, Vibhudutta Awasthi⁶, Madhan Subramanian⁴, Anna Csiszar^1,^2,^3,⁷, Priya Balasubramanian^1,^2,³

¹Department of Neurosurgery, Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
²Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
³The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
⁴Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 73104, USA
⁵Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
⁶Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
⁷International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

Received: August 13, 2024Accepted: January 29, 2025Published: February 19, 2025

https://doi.org/10.18632/aging.206203

Copyright: © 2025 Natarajan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction. Hence, in the present study, we aimed to test whether thermogenic stimulation, an intervention known to improve adipose and systemic metabolism by increasing cellular energy expenditure, could mitigate brain endothelial dysfunction and improve cognition in the aging population. Eighteen-month-old C57BL/6J mice were treated with saline or β3-adrenergic agonist (CL 316, 243, CL) for 6 weeks followed by functional analysis to assess endothelial function and cognition. CL treatment improved neurovascular coupling responses and rescued brain glucose uptake in aged animals. In addition, CL treatment also attenuated blood-brain barrier leakage and associated neuroinflammation in the cortex and increased microvascular density in the hippocampus of aged mice. More importantly, these beneficial changes in microvascular function translated to improved cognitive performance in aged mice. Our results suggest that β3-adrenergic agonist treatment improves multiple aspects of cerebromicrovascular function and can be potentially repurposed for treating age-associated cognitive decline.