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Treatment with the poly(ADP-ribose) polymerase inhibitor PJ-34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging

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Abstract

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) plays an important role in the maintenance of healthy cognitive function. Strong evidence demonstrates that age-related cerebromicrovascular endothelial dysfunction and consequential impairment of NVC responses contribute importantly to cognitive decline. Recent studies demonstrate that NAD+ availability decreases with age in the vasculature and that supplemental NAD+ precursors can ameliorate cerebrovascular dysfunction, rescuing NVC responses and improving cognitive performance in aged mice. The mechanisms underlying the age-related decline in [NAD+] in cells of the neurovascular unit are likely multifaceted and may include increased utilization of NAD+ by activated poly (ADP-ribose) polymerase (PARP-1). The present study was designed to test the hypothesis that inhibition of PARP-1 activity may confer protective effects on neurovascular function in aging, similar to the recently demonstrated protective effects of treatment with the NAD+ precursor nicotinamide mononucleotide (NMN). To test this hypothesis, 24-month-old C57BL/6 mice were treated with PJ-34, a potent PARP inhibitor, for 2 weeks. 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. Treatment with PJ-34 improved NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory. PJ-34 treatment also improved endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, PARP-1 activation, likely by decreasing NAD+ availability, contributes to age-related endothelial dysfunction and neurovascular uncoupling, exacerbating cognitive decline. The cerebromicrovascular protective effects of pharmacological inhibition of PARP-1 highlight the preventive and therapeutic potential of treatments that restore NAD+ homeostasis as effective interventions in patients at risk for vascular cognitive impairment (VCI).

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Acknowledgements

This work was supported by grants from the American Heart Association (ST), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC, R01-NS100782 to ZU), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938, to AY and JW), the Presbyterian Health Foundation (to ZU, AC, AY), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337). The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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  1. Stefano Tarantini, Andriy Yabluchanskiy, Tamas Csipo and Gabor Fulop contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA

    Stefano Tarantini, Andriy Yabluchanskiy, Tamas Csipo, Gabor Fulop, Tamas Kiss, Priya Balasubramanian, Jordan DelFavero, Chetan Ahire, Anna Ungvari, Ádám Nyúl-Tóth, Anna Csiszar & Zoltan Ungvari

  2. International Training Program in Geroscience, Department of Public Health/Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary

    Stefano Tarantini, Tamas Csipo & Zoltan Ungvari

  3. International Training Program in Geroscience, Division of Clinical Physiology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary

    Tamas Csipo, Gabor Fulop & Attila Tóth

  4. Heart and Vascular Center, Semmelweis University, Budapest, Hungary

    Gabor Fulop

  5. International Training Program in Geroscience, Department of Medical Physics and Informatics/Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary

    Tamas Kiss, Eszter Farkas & Zoltan Ungvari

  6. Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary

    Ádám Nyúl-Tóth

  7. Institute of Clinical Experimental Research/Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary

    Zoltan Benyo & Anna Csiszar

  8. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari

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  1. Stefano Tarantini
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Tarantini, S., Yabluchanskiy, A., Csipo, T. et al. Treatment with the poly(ADP-ribose) polymerase inhibitor PJ-34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging. GeroScience 41, 533–542 (2019). https://doi.org/10.1007/s11357-019-00101-2

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