Fri. Jul 19th, 2024

Combination of NAD+ and NADPH Offers Greater Neuroprotection
in Ischemic Stroke Models by Relieving Metabolic Stress


Both reduced nicotinamide adenine dinucleotide phosphate (NADPH) and β-nicotinamide adenine dinucleotide hydrate (NAD+) have been reported to have potent neuroprotective effects against ischemic neuronal injury. Both NADPH and NAD+ are essential cofactors for anti-oxidation and cellular energy metabolism. We investigated if combined NADPH and NAD+ could offer better neuroprotective effects on cellular and animal models of ischemic stroke. In vitro studies with primary cultured neurons demonstrated that NAD+ was effective in protecting neurons against oxygen-glucose deprivation/reoxygenation (OGD/R) injury when given during the early time period of reoxygenation. In vivo studies in mice also suggested that NAD+ was effective for ameliorating ischemic brain damage when administered within 2 h after reperfusion. The combination of NADPH and NAD+ provided not only greater beneficial effects but also larger therapeutic window in both cellular and animal models of stroke. The combination of NADPH and NAD+ significantly increased the levels of adenosine triphosphate (ATP) and reduced the levels of reactive oxygen species (ROS) and oxidative damage of macromolecules. Furthermore, the combined medication significantly reduced long-term mortality, improved the functional recovery, and inhibited signaling pathways involved in apoptosis and necroptosis after ischemic stroke. The present study indicates that the combination of NAD+ and NADPH can produce greater therapeutic effects with smaller dose of NADPH; on the other hand, NADPH can significantly prolong the therapeutic window of NAD+. The current results suggest that the combination of NADPH and NAD+ may provide a novel effective therapy for ischemic stroke.

Keywords: Apoptosis; NAD+; NADPH; ROS; Stroke.

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    1. Stroke. 2001 Nov;32(11):2709-10 – PubMed
    1. Cell Mol Life Sci. 2012 Jul;69(13):2245-60 – PubMed
    1. Front Biosci. 2007 Jan 01;12 :2728-34 – PubMed
    1. Free Radic Biol Med. 2005 Nov 15;39(10):1291-304 – PubMed
    1. Toxicol In Vitro. 2007 Sep;21(6):1003-9 – PubMed
    1. Stroke. 2016 Jan;47(1):187-95 – PubMed
    1. Nat Rev Neurosci. 2003 May;4(5):399-415 – PubMed
    1. Circ Res. 2009 Aug 28;105(5):481-91 – PubMed
    1. Br J Pharmacol. 1999 Sep;128(2):419-27 – PubMed
    1. J Neurosci. 2007 Aug 29;27(35):9278-93 – PubMed
    1. Mutat Res. 1997 Jan 15;388(1):33-44 – PubMed
    1. J Neurotrauma. 2012 May 1;29(7):1401-9 – PubMed
    1. Stroke. 2008 Mar;39(3):1012-21 – PubMed
    1. J Neurosci. 2010 Feb 24;30(8):2967-78 – PubMed
    1. J Neurochem. 2012 Jan;120(1):70-7 – PubMed
    1. J Biol Chem. 2012 Sep 14;287(38):32124-35 – PubMed
    1. Antioxid Redox Signal. 2008 Feb;10(2):179-206 – PubMed
    1. Neurol Res. 1997 Dec;19(6):641-8 – PubMed
    1. Neurochem Res. 2011 Dec;36(12 ):2270-7 – PubMed
    1. Stroke. 2001 Apr;32(4):1005-11 – PubMed
    1. J Neurosci. 2000 May 1;20(9):3139-46 – PubMed
    1. Cell Metab. 2015 Jul 7;22(1):31-53 – PubMed
    1. J Biol Chem. 2004 Apr 30;279(18):18895-902 – PubMed
    1. Stroke. 2007 Aug;38(8):2329-36 – PubMed

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