Cellular NAD Replenishment Confers Marked Neuroprotection Against Ischemic Cell Death

Abstract

Background and Purpose-NADϩ is an essential cofactor for cellular energy production and participates in various signaling pathways that have an impact on cell survival. After cerebral ischemia, oxidative DNA lesions accumulate in neurons because of increased attacks by ROS and diminished DNA repair activity, leading to PARP-1 activation, NAD

Omega-3 Fatty Acids Protect the Brain against Ischemic Injury by Activating Nrf2 and Upregulating Heme Oxygenase 1

“…This protection was not dependent on rCBF changes, as wild-type and fat-1 mice demonstrated equivalent rCBF changes ( Fig. 1F-H ), which were measured by IAP autoradiography 15 min after the onset of MCAO (Sawada et al, 2000;Stetler et al, 2008). These data strongly indicate that n-3 PUFAs alleviate acute brain injury induced by focal ischemia in mice.…”

“…For the long-term studies (21 d), the corner test and rotarod test (IITC Life Science) were performed up to 7 d after MCAO. The Morris water maze test was performed from day 15 to day 21 following MCAO by a blinded observer to evaluate cognitive function (Stetler et al, 2008). Following this test, animals were killed by perfusion and the brain sections (5 m) were stained with antimicrotubule-associated protein 2 (MAP2).…”

“…EGFPtagged human Nrf2 (pcDNA3-EGFP-C4-Nrf2, Addgene) was inserted into the lentiviral transfer vector FSW under the control of neuronspecific synapsin I promoter (Furukawa and Xiong, 2005;Stetler et al, 2008;. To detect whether lipid electrophiles induce nuclear translocation, neuronal cultures were infected for 3 d with lenti-Nrf2, and then treated with 4-HNE or 4-HHE (5 M) for 1 h. The cultures were then counterstained with DAPI and photographed.…”

In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences

“…It has been shown that, by supplying NAD + precursors or intermediates and/or introducing PARPs or CD38 inhibitor, one could enhance the NAD + biosynthesis and/or inhibit its consumption, thus boosting the intracellular NAD + level (6,10,11,43). Such interventions are suggested to promote therapeutic effects of lifespan extension and neuroprotection and could potentially be used with other physiological managements, such as calorie restriction, fasting, or exercise, to compensate for the natural decline of brain NAD + in normal aging and prevent or treat age-related metabolic disorders (3,4,33,44,45).…”

“…More recently, after several protein families associated with cell survival were found to use NAD + as their main substrate with activities also regulated by the availability of the NAD + , the full extent of the NAD's function as a metabolic regulator began to unfold (3)(4)(5). A growing number of studies have indicated that NAD + can modulate metabolic signaling pathways and mediate important cellular processes, including calcium homeostasis, gene expression, aging, degeneration, and cell death; therefore, the cellular NAD could serve as a therapeutic target for treating various metabolic or age-related diseases and promoting longevity (6)(7)(8)(9)(10)(11)(12).…”