Biocompatibility of Nicotinamide Riboside at Varying Dosages via Intravenous Administration

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Abstract

Nicotinamide riboside (NR) serves as a precursor to NAD+. Numerous studies in the literature report on the oral administration of NR, demonstrating its beneficial effects on the progression of diseases such as cardiovascular, neurodegenerative, renal, hepatic, and others. Previously, a hypothesis was proposed by the authors suggesting a protective effect of intravenous NR administration against doxorubicin-induced myocardial damage. However, under this mode of administration, special attention must be given to the biocompatibility of NR when used at therapeutically effective doses. Thus, the aim of this study was to assess the biocompatibility of various NR doses with repeated intravenous administration in Wistar rats. The study employed doses of 150, 300, 450, and 600 mg/kg of NR (cumulative doses of 900, 1800, 2700, and 3600 mg/kg, respectively). During the study, the biocompatibility of NR was demonstrated at doses of 150, 300, and 450 mg/kg with repeated intravenous administration in rats. Even at the highest dose of 450 mg/kg, repeated intravenous administration showed no adverse effects on the parasympathetic ganglia of the autonomic nervous system in the heart. However, increasing the dose of NR led to several adverse side effects, including animal mortality, reduced tolerance to physical exertion, impaired cardiovascular function, and morphological and functional changes in the myocardium, liver, and kidneys.

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About the authors

E. Yu. Podyacheva

Almazov National Medical Research Centre

Author for correspondence.
Email: e-ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

N. Yu. Semenova

Almazov National Medical Research Centre

Email: ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

D. V. Mukhametdinova

Almazov National Medical Research Centre

Email: ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

I. A. Zelinskaya

Almazov National Medical Research Centre

Email: ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

L. A. Murashova

Almazov National Medical Research Centre

Email: ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

A. V. Onopchenko

Almazov National Medical Research Centre

Email: ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

E. V. Shchelina

Almazov National Medical Research Centre

Email: ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

M. O. Martynov

Almazov National Medical Research Centre

Email: ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

V. A. Dyachuk

Almazov National Medical Research Centre

Email: ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

V. A. Zinserling

Almazov National Medical Research Centre

Email: e-ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

Ya. G. Toropova

Almazov National Medical Research Centre

Email: e-ekaterinapodyachevaspb@gmail.com
Russian Federation, Saint Petersburg

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Supplementary files

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2. Fig. 1. (a) - Dynamics of body weight of animals of experimental groups. * - compared to the control group (Control), * - p < 0.05, ** - p < 0.01. Data are presented as Mean ± SD. (b) - Kaplan-Meier estimation plot for 600NR.

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3. Fig. 2. (a) - Dynamics of left ventricular shortening fraction (FS) in animals of experimental groups. (b) - Dynamics of left ventricular end-systolic size (LVIDs) of animals of experimental groups. (c) - Dynamics of left ventricular end-diastolic size (LVIDd) of animals of experimental groups. (d) - Dynamics of anterior wall size in diastole (IVS) of animals of experimental groups. (e) - Dynamics of posterior wall size in diastole (LVPW) of animals of experimental groups. * - compared to baseline, ** - p < 0.01; *** - p < 0.001. Data are presented as Mean ± SD.

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4. Fig. 3. (a) - Cumulative contractility curve and area under the curve (AUC) values in animals of experimental groups. (b) - Cumulative relaxation curve and area under the curve (AUC) values in animals of experimental groups. * - compared to control group (Control), p < 0.05.

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5. Fig. 4. Percentage of fibrosis in the epicardial (a), perivascular (b) and interstitial (c) zones of the left ventricle in animals of the experimental groups. (d) - Heart weight in animals of experimental groups. * - Compared with the control group (Control); # - compared with the 150NR group; @ - compared with the 300NR group; ^ - compared with the 450NR group (*/#/@/^ - p < 0.01; **/###/@@@/^^^ - p < 0.01; ***/####/@@@@/^^^^ - p < 0.001). Data are presented as median [25th percentile; 75th percentile].

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6. Fig. 5. (a) - Representative photographs of the kidney of animals of experimental groups. Haematoxylin-eosin staining, ×50, ×100. (b) - Representative photographs of the liver of animals of experimental groups. Haematoxylin-eosin staining, ×100.

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7. Fig. 6. Biochemical indices of animals of experimental groups. (a) - ALT. (b) - AST. (c) - Creatinine. * - compared to control group (Control); # - compared to 150NR group; @ - compared to 300NR group (*/#/@ - p < 0.05; **/###/@@ - p < 0.01; ***/###/@@@@ - p < 0.001). Data are presented as median (25th percentile; 75th percentile).

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8. Fig. 7. Evaluation of apoptosis by TUNEL assay in animals of experimental groups. (a) - TUNEL-positive cells are seen as nuclei stained green. Arrows indicate neurons in apoptosis, asterisk indicates muscle autofluorescence, ×200. (b) - The percentage of TUNEL-positive cells was also calculated and shown as a graph. Data are presented as Mean ± SD.

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