AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Journal of Neurorestoratology Article
Article Link
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Research | Open Access

Liposome-based loading enhances the distribution of nicotinamide riboside chloride into the brain and its neuroprotective effects in cerebral ischemic mice

Xinxin Xiea,1, Qianqian Konga,1, Yan Chenb, Zhongzheng Yangc, Zeqiang Wuc, Yue Xiaoc, Yajun Chend, Zhiyuan Yua,e, Xiang Luoa,e, Wensheng Qua,e( )
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
Department of Pharmacology, Tongji Medical University, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
Wuhan Biobank, Human Genetic Resource Bank, Wuhan 430030, Hubei, China
Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430030, Hubei, China
Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China

1 These authors contributed equally to this work.

Show Author Information

Abstract

Objective

Nicotinamide riboside (NR) is neuroprotective; however, its low permeability through the blood‒brain barrier restricts its therapeutic efficacy in central nervous system diseases. Compared with oral NR administration, liposome-based NR loading is hypothesized to improve its pharmacological properties during cerebral ischemia, especially when administered intravenously.

Methods

NR chloride (NRC) was encapsulated in an optimized liposome composition and administered by bolus intravenous injection. This was followed by examination of its pharmacokinetics, organ distribution, and effects on cerebral ischemia in mice.

Results

Compared with conventional NRC solution, the liposome form led to a 2.76-fold higher Cmax and a 5.32-fold higher AUC0–24h in plasma after a bolus injection of 40 mg/kg. In healthy mouse brain, it caused a significant elevation of Cmax (2.93-fold) and AUC0.25–24h (2.68-fold). In cerebral ischemia model mice, NRC liposomes increased the drug concentration at 1 and 6 h post-ischemia, increased tissue NAD+ and ATP levels, reduced infarct volume (by a further decrease of 35.4%), ensured neuronal survival, attenuated glial activation, and significantly improved behavioral recovery compared with conventional NRC treatment.

Conclusion

Liposome loading enhances the brain distribution and therapeutic effects of NRC, which strengthens its possibility for clinical translation and neurorestoration in stroke.

Keywords

NeuroprotectionPharmacokineticsLiposomeCerebral ischemiaNicotinamide adenine dinucleotideNicotinamide riboside

Electronic Supplementary Material

Download File(s)
jnrt-12-2-100111_ESM1.docx (167.9 KB)
jnrt-12-2-100111_ESM2.docx (131 KB)
jnrt-12-2-100111_ESM3.docx (11.2 KB)
jnrt-12-2-100111_ESM4.docx (12.8 KB)
jnrt-12-2-100111_ESM5.docx (13.7 KB)

References

1

Katan M, Luft A. Global burden of stroke. Semin Neurol. 2018;38(2):208–211. https://doi.org/10.1055/s-0038-1649503.
Crossref Google Scholar
2

Zhang Q, Jia M, Wang YF, et al. Cell death mechanisms in cerebral ischemiareperfusion injury. Neurochem Res. 2022;47(12):3525–3542. https://doi.org/10.1007/s11064-022-03697-8.
Crossref Google Scholar
3

Giles JA, Vellimana AK, Adeoye OM. Endovascular treatment of acute stroke. Curr Neurol Neurosci Rep. 2022;22(1):83–91. https://doi.org/10.1007/s11910-022-01168-9.
Crossref Google Scholar
4

Hurd MD, Goel I, Sakai Y, et al. Current status of ischemic stroke treatment:from thrombolysis to potential regenerative medicine. Regen Ther. 2021;18:408–417. https://doi.org/10.1016/j.reth.2021.09.009.
Crossref Google Scholar
5

Hosseini L, Vafaee MS, Mahmoudi J, et al. Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions. Biogerontology. 2019;20(4):381–395. https://doi.org/10.1007/s10522-019-09805-6.
Crossref Google Scholar
6

Sauve AA. NAD+ and vitamin B3: from metabolism to therapies. J Pharmacol Exp Therapeut. 2008;324(3):883–893. https://doi.org/10.1124/jpet.107.120758.
Crossref Google Scholar
7

Yang Y, Sauve AA. NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta. 2016;1864(12):1787–1800. https://doi.org/10.1016/j.bbapap.2016.06.014.
Crossref Google Scholar
8

Reiten OK, Wilvang MA, Mitchell SJ, et al. Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mech Ageing Dev. 2021;199:111567. https://doi.org/10.1016/j.mad.2021.111567.
Crossref Google Scholar
9

Mehmel M, Jovanović N, Spitz U. Nicotinamide riboside-the current state of research and therapeutic uses. Nutrients. 2020;12(6):1616. https://doi.org/10.3390/nu12061616.
Crossref Google Scholar
10

Cheng YH, Zhao JH, Zong WF, et al. Acute treatment with nicotinamide riboside chloride reduces hippocampal damage and preserves the cognitive function of mice with ischemic injury. Neurochem Res. 2022;47(8):2244–2253. https://doi.org/10.1007/s11064-022-03610-3.
Crossref Google Scholar
11

Qu W, Ralto KM, Qin T, et al. NAD+ precursor nutritional supplements sensitize the brain to future ischemic events. J Cerebr Blood Flow Metabol. 2023;43(2_suppl l):37–48. https://doi.org/10.1177/0271678x231156500.
Crossref Google Scholar
12

Martens CR, Denman BA, Mazzo MR, et al. Chronicnicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286. https://doi.org/10.1038/s41467-018-03421-7.
Crossref Google Scholar
13

Airhart SE, Shireman LM, Risler LJ, et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017;12(12):e0186459. https://doi.org/10.1371/journal.pone.0186459.
Crossref Google Scholar
14

Fang J, Wu HM, Zhang JN, et al. A reduced form of nicotinamide riboside protects the cochlea against aminoglycoside-induced ototoxicity by SIRT1 activation. Biomed Pharmacother. 2022;150:113071. https://doi.org/10.1016/j.biopha.2022.113071.
Crossref Google Scholar
15

Braidy N, Berg J, Clement J, et al. Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases:rationale, biochemistry, pharmacokinetics, and outcomes. Antioxidants Redox Signal. 2019;30(2):251–294. https://doi.org/10.1089/ars.2017.7269.
Crossref Google Scholar
16

Braidy N, Liu Y. Can nicotinamide riboside protect against cognitive impairment? Curr Opin Clin Nutr Metab Care. 2020;23(6):413–420. https://doi.org/10.1097/MCO.0000000000000691.
Crossref Google Scholar
17

Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. Faseb J. 2008;22(3):659–661. https://doi.org/10.1096/fj.07-9574LSF.
Crossref Google Scholar
18

Yang G, Yang T, Zhang WD, et al. In vitro and in vivo antitumor effects of folatetargeted ursolic acid stealth liposome. J Agric Food Chem. 2014;62(10):2207–2215. https://doi.org/10.1021/jf405675g.
Crossref Google Scholar
19

Schaar KL, Brenneman MM, Savitz SI. Functional assessments in the rodent stroke model. Exp Transl Stroke Med. 2010;2(1):13. https://doi.org/10.1186/2040-7378-2-13.
Crossref Google Scholar
20

Chi YL, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. Curr Opin Clin Nutr Metab Care. 2013;16(6):657–661. https://doi.org/10.1097/MCO.0b013e32836510c0.
Crossref Google Scholar
21

Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7:12948. https://doi.org/10.1038/ncomms12948.
Crossref Google Scholar
22

Zhou Q, Zhu L, Qiu WW, et al. Nicotinamide riboside enhances mitochondrial proteostasis and adult neurogenesis through activation of mitochondrial unfolded protein response signaling in the brain of ALS SOD1G93A mice. Int J Biol Sci. 2020;16(2):284–297. https://doi.org/10.7150/ijbs.38487.
Crossref Google Scholar
23

Schondorf DC, Ivanyuk D, Baden P, et al. The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson's disease. Cell Rep. 2018;23(10):2976–2988. https://doi.org/10.1016/j.celrep.2018.05.009.
Crossref Google Scholar
24

Hou YJ, Lautrup S, Cordonnier S, et al. NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci USA. 2018;115(8):E1876–E1885. https://doi.org/10.1073/pnas.1718819115.
Crossref Google Scholar
25

Conze D, Brenner C, Kruger CL. Safety and metabolism of long-term administration of NIAGEN (nicotinamide riboside chloride) in a randomized, doubleblind, placebo-controlled clinical trial of healthy overweight adults. Sci Rep. 2019;9(1):9772. https://doi.org/10.1038/s41598-019-46120-z.
Crossref Google Scholar
26

So PW, Ekonomou A, Galley K, et al. Intraperitoneal delivery of acetateencapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke. Int J Nanomed. 2019;14:1979–1991. https://doi.org/10.2147/IJN.S193965.
Crossref Google Scholar
27

Milano G, Innocenti F, Minami H. Liposomal irinotecan (Onivyde): exemplifying the benefits of nanotherapeutic drugs. Cancer Sci. 2022;113(7):2224–2231. https://doi.org/10.1111/cas.15377.
Crossref Google Scholar
28

He H, Yuan DF, Wu Y, et al. Pharmacokinetics and pharmacodynamics modeling and simulation systems to support the development and regulation of liposomal drugs. Pharmaceutics. 2019;11(3):110. https://doi.org/10.3390/pharmaceutics11030110.
Crossref Google Scholar
29

Teleanu RI, Preda MD, Niculescu AG, et al. Current strategies to enhance delivery of drugs across the blood-brain barrier. Pharmaceutics. 2022;14(5):987. https://doi.org/10.3390/pharmaceutics14050987.
Crossref Google Scholar
30

He Y, Zhang YQ, Li WX, et al. Evaluating blood-brain barrier disruption and infarction volume concurrently in rats subjected to ischemic stroke using an optical imaging system. J Neurosci Methods. 2022;378:109630. https://doi.org/10.1016/j.jneumeth.2022.109630.
Crossref Google Scholar
31

Rigoulet M, Bouchez CL, Paumard P, et al. Cell energy metabolism: an update. Biochim Biophys Acta Bioenerg. 2020;1861(11):148276. https://doi.org/10.1016/j.bbabio.2020.148276.
Crossref Google Scholar
32

Chen SD, Yang DI, Lin TK, et al. Roles of oxidative stress, apoptosis, PGC-1a and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci. 2011;12(10):7199–7215. https://doi.org/10.3390/ijms12107199.
Crossref Google Scholar
33

Covarrubias AJ, Perrone R, Grozio A, et al. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021;22(2):119–141. https://doi.org/10.1038/s41580-020-00313-x.
Crossref Google Scholar
34

Stocks B, Ashcroft SP, Joanisse S, et al. Nicotinamide riboside supplementation does not alter whole-body or skeletal muscle metabolic responses to a single bout of endurance exercise. J Physiol. 2021;599(5):1513–1531. https://doi.org/10.1113/JP280825.
Crossref Google Scholar
35

Ratajczak J, Joffraud M, Trammell SA, et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun. 2016;7:13103. https://doi.org/10.1038/ncomms13103.
Crossref Google Scholar
Journal of Neurorestoratology
Volume 12 Issue 2,
June 2024
Article number: 100111
DOI: 10.1016/j.jnrt.2024.100111
Cite this article:
Xie X, Kong Q, Chen Y, et al. Liposome-based loading enhances the distribution of nicotinamide riboside chloride into the brain and its neuroprotective effects in cerebral ischemic mice. Journal of Neurorestoratology, 2024, 12(2): 100111. https://doi.org/10.1016/j.jnrt.2024.100111

203

Views

1

Crossref

1

Web of Science

1

Scopus

Altmetrics
Received: 23 November 2023
Revised: 21 February 2024
Accepted: 26 February 2024
Published: 15 March 2024
© 2024

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Return