Tarantini, Stefano and Balasubramanian, Priya and Delfavero, Jordan and Csípő, Tamás and Yabluchanskiy, Andriy and Kiss, Tamás and Nyúl-Tóth, Ádám and Mukli, Péter and Tóth, Péter József and Benyó, Zoltán and Csiszar, Anna and Ungvári, Zoltán István (2021) Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice. GEROSCIENCE: OFFICIAL JOURNAL OF THE AMERICAN AGING ASSOCIATION (AGE), 43 (5). pp. 2427-2440. ISSN 2509-2715
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Abstract
Moment-to-moment adjustment of regional cerebral blood flow to neuronal activity via neurovascular coupling (NVC or "functional hyperemia") has a critical role in maintenance of healthy cognitive function. Aging-induced impairment of NVC responses importantly contributes to age-related cognitive decline. Advanced aging is associated with increased prevalence of senescent cells in the cerebral microcirculation, but their role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that a validated senolytic treatment can improve NVC responses and cognitive performance in aged mice. To achieve this goal, aged (24-month-old) C57BL/6 mice were treated with ABT263/Navitoclax, a potent senolytic agent known to eliminate senescent cells in the aged mouse brain. Mice were behaviorally evaluated (radial arms water maze) and NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. ABT263/Navitoclax treatment improved NVC response, which was associated with significantly improved hippocampal-encoded functions of learning and memory. ABT263/Navitoclax treatment did not significantly affect endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, increased presence of senescent cells in the aged brain likely contributes to age-related neurovascular uncoupling, exacerbating cognitive decline. The neurovascular protective effects of ABT263/Navitoclax treatment highlight the preventive and therapeutic potential of senolytic treatments (as monotherapy or as part of combination treatment regimens) as effective interventions in patients at risk for vascular cognitive impairment (VCI).
| Item Type: | Article |
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| Additional Information: | Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK 731042, United States Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, United States Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary Department of Pediatrics, University of Szeged, Szeged, Hungary First Department of Pediatrics, Semmelweis University, Budapest, Hungary International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), Szeged, Hungary International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Physiology, Semmelweis University, Budapest, Hungary Department of Neurosurgery, University of Pécs Clinical Center, Pecs, Hungary MTA-PTE Clinical Neuroscience MR Research Group, Pecs, Hungary International Training Program in Geroscience/Vascular Cognitive Impairment and Neurodegeneration Program, Department of Translational Medicine, Semmelweis University, Budapest, Hungary Export Date: 3 January 2022 Correspondence Address: Tarantini, S.; Vascular Cognitive Impairment and Neurodegeneration Program, 975 NE 10th Street, BRC 1311, United States; email: stefano-tarantini@ouhsc.edu Chemicals/CAS: navitoclax, 923564-51-6, 1000696-69-4, 1093851-28-5 Tradenames: abt 263 |
| Uncontrolled Keywords: | MICROCIRCULATION; Aging; endothelial dysfunction; senescence; Vascular cognitive impairment; Functional hyperemia; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3020 Biophysics / biofizika R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan, neurológia, pszichiátria |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 07 Feb 2022 11:23 |
| Last Modified: | 07 Feb 2022 11:23 |
| URI: | http://real.mtak.hu/id/eprint/137500 |
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