NAD+ precursors mitigate the in vitro and in vivo reproductive defects: Limitations and possible solutions

Abstract

In mammalian cells, nicotinamide adenine dinucleotide (NAD⁺) participates in the regulation of diverse cellular processes such as ATP production, oxidative stress resistance, DNA repair, metabolic homeostasis, and inflammation. Due to these properties, exogenously applied NAD⁺ precursors (nicotinic acid, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide) can protect organs and cells of mammalian against detrimental effects of various stress factors and diseases. For instance, NAD⁺ and its precursors have critical importance for the in vivo and in vitro fertilization success of mammals. This review summarizes that the natural aging process, diseases, and toxic compounds cause the detrimental effects in the reproductive parameters of the in vivo models, such as the meiotic defects and the reductions in cellular NAD⁺ level, mitochondrial functions, sperm and oocyte quality, blastocyst and embryo formation rate, implantation success, whereas the intragastric, intraperitoneal or oral administration of NAD⁺ precursors prevents or attenuates these detrimental effects. Similarly, the supplementation of NAD⁺ precursors can protect the oocytes and sperms against the cryopreservation process, aging and toxic compounds in the in vitro and also enhances blastocyst and embryo formation in vitro. This review study also revealed that the ability of NAD⁺ precursors-loaded drug delivery systems to prevent reproductive defects has not yet been investigated in literature. Therefore, we recommend the development of NAD⁺ precursor-loaded drug delivery systems targeting reproductive system organs and/or cell organelles (mitochondria, endoplasmic reticulum and nucleus). To achieve this, hormone receptors in testicular and ovarian cells can be targeted. Similarly, triphenylphosphonium (TPP⁺) can be used to specifically target mitochondria.

Keywords: Assisted reproductive technology; Drug delivery; Infertility; NAD(+) precursors; Oxidative stress; Sirtuins.