Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy

Abstract

Doxorubicin, which is widely used to treat a broad spectrum of malignancies, has pronounced dose-dependent side effects leading to chronic heart failure development. Nicotinamide riboside (NR) is one of the promising candidates for leveling the cardiotoxic effect. In the present work, we performed a comparative study of the cardioprotective and therapeutic actions of various intravenous NR administration modes in chronic doxorubicin-induced cardiomyopathy in Wistar rats. The study used 60 mature male SPF Wistar rats. The animals were randomized into four groups (a control group and three experimental groups) which determined the doxorubicin (intraperitoneally) and NR (intravenous) doses as well as the specific modes of NR administration (combined, preventive). We demonstrated the protective effect of NR on the cardiovascular system both with combined and preventive intravenous drug administration, which was reflected in a fibrous tissue formation decrease, reduced fractional-shortening decrease, and better antioxidant system performance. At the same time, it is important to note that the preventive administration of NR had a more significant protective effect on the animal organism as a whole. This was confirmed by better physical activity parameters and vascular bed conditions. Thus, the data obtained during the study can be used for further investigation into chronic doxorubicin-induced cardiomyopathy prevention and treatment approaches.

Nicotinamide Mononucleotide Administration Prevents Doxorubicin-Induced Cardiotoxicity and Loss in Physical Activity in Mice

“…Nevertheless, it is important to mention that compared to previous reports [24,68,74,83,84] using biosynthetic precursors, such as NMN, NR and Nicotinic acid riboside (NAR) in animal models of Doxo-induced toxicity, we demonstrated that NMN supplementation is sufficient to improve the physical capacity impaired by Doxo using a clinically relevant route of administration and a concentration (500 mg/kg/day) that is below the recently reported NOAEL (No-Observable Adverse Effect Level) for NMN in Sprague Dawley rats [37].…”

“…However, to the best of our knowledge, the results presented here are the first to demonstrate that the oral NMN administration preserves the exercise capacity in a context of chemotherapeutic regimen. Interestingly, a recent study has shown that the intravenous administration of another biosynthetic NAD+ precursor, NR (300 mg/kg) in Wistar rats subjected to a chronic Doxo treatment (10 mg/kg cumulative dose) has little to no effect on exercise capacity at 30-and 60 days post Doxo administration [83]. Therefore, additional studies are needed to compare different NAD+ biosynthetic precursors in the same experimental conditions and animal models in order to identify the most efficient NAD+-boosting strategy to counteract Doxo-induced side-effects.…”

FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM

“…and TNF-α, via modulation of HIF/VEGF and cGMP/cAMP/SIRT signaling pathways [54]. Nicotinamide riboside administration was shown to exert a cardioprotective property against chronic DOXinduced cardiomyopathy [55]. These findings provide new ways of DOX-induced cardiomyopathy prevention and treatment approaches.…”

Nicotinamide Mononucleotide Supplementation Alleviates Doxorubicin-Induced Multi-Organ Fibrosis

“…Tissue fibrosis was reported in mice exposed to DOX [21,30], and epithelial-to-mesenchymal transition (EMT) along with endothelial-to-mesenchymal transition (EndoMT) are crucial in excessive myofibroblast generation and progression of fibrosis. The mesenchymal marker alpha-smooth muscle actin (α-SMA) was activated in resident fibroblasts during cardiac fibrosis [31].…”

“…As a fundamental molecule in cells, NAD + plays key roles in energy metabolism and mitochondrial function and is involved in counteracting DNA damage and oxidative stress [20]. Supplementing the NAD + precursor nicotinamide riboside (NR) may efficiently alleviate DOX-induced cardiomyopathy by promoting DNA repair and mitochondrial homeostasis [21]. Nicotinic acid riboside (NAR) treatment attenuates DOX-induced myocardial injury through the Nrf-2/p62 pathway [22].…”