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

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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).

Original languageEnglish
JournalGeroScience
DOIs
Publication statusAccepted/In press - Jan 1 2019

Keywords

  • Cellular energetics
  • Endothelial dysfunction
  • Functional hyperemia
  • Microcirculation
  • Oxidative stress
  • ROS
  • Senescence

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this