P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage

Abstract

SUMMARY The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photo-crosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.

Mitochondrion as a Target for Heart Failure Therapy – Role of Protein Lysine Acetylation –

“…79 Recently, a small molecule activator of the NAD + biosynthetic pathway was shown to be neuroprotective. 80 Whether decreases in NAD + /NADH ratio or increases in NAD + -sensitive LysAc occur in the failing heart has not been directly determined. Previous studies have targeted histone acetylation for autophagy in the treatment of cardiac hypertrophy and ischemia/reperfusion injury.…”

“…The process is affected by the cellular level of acetyl-CoA and/or the activity of acetyltransferases. Detailed information on the enzymes and substrates involved in protein LysAc is summarized in Table. [69][70][71][72][73][74][75][76][77][78][79][80][81][82][83] While the presence of histone acetyltransferases (HAT) in the nucleus is well established, the mode of acetyl group transfer for non-histone proteins is complex. tricarboxylic acid (TCA) cycle and produces the reducing equivalents NADH/FADH2.…”

“…114 Stimulating the NAD + biosynthetic pathway in the absence of calorie restriction increases NAD + and promotes protein deacetylation by the sirtuins. 76, 80 Treatment of the heart with complex I deficiency with the NAD + precursor NMN normalizes NAD + / NADH ratio and restores the sensitivity of mPTP to calcium challenge. 92 NMN treatment also attenuates diet-/age-induced diabetes 76 and the effects of aging.…”

Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors

“…Tangential support for this hypothesis includes a study in which deletion of neurofibromin 1 from adult-born cells increased levels of adult neurogenesis and had an antidepressant-like effect on behavior; however, this manipulation not only increased the number of adultborn neurons, but also affected these cells in other ways, such as by activating ERK signaling (Li et al, 2012). More recently, the P7C3 compound has been shown to increase adult neurogenesis and has an antidepressant-like effect on social interaction behavior following social defeat; however, P7C3 likely exerts its effects through multiple biological processes including, but not limited to, neurogenesis (Walker et al, 2014;Wang et al, 2014;Yin et al, 2014).…”

Circadian Mechanisms in Bioenergetics and Cell Metabolism

“…New pharmacologic (Wang et al 2014) and genetic means to raise NAD + both globally in the whole animal and selectively within either liver or skeletal muscle are now available and will be powerful tools in evaluating the potential to boost NAD + as a therapeutic strategy in myopathy and liver defects of circadian mutant animals. Finally, in addition to its function as a cofactor for the class III histone deacetylases, NAD + is a cofactor for the poly-ADP-ribosylases, critical factors in DNA repair and stress response, though the possible interaction between rhythmic regulation of NAD + and PARP activity is not known.…”