Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases

Ozlem Altay; Hong Yang; Serkan Yildirim; Cemil Bayram; Ismail Bolat; Sena Oner; Ozlem Ozdemir Tozlu; Mehmet Enes Arslan; Ahmet Hacimuftuoglu; Saeed Shoaie; Cheng Zhang; Jan Borén; Mathias Uhlén; Hasan Turkez; Adil Mardinoglu

doi:10.3390/biomedicines12040927

Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases

Ozlem Altay, Hong Yang, Serkan Yildirim, Cemil Bayram, Ismail Bolat, Sena Oner, Ozlem Ozdemir Tozlu, Mehmet Enes Arslan, Ahmet Hacimuftuoglu, Saeed Shoaie, Cheng Zhang, Jan Borén, Mathias Uhlén, Hasan Turkez, Adil Mardinoglu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.

Original language	English
Article number	927
Journal	Biomedicines
Volume	12
Issue number	4
Early online date	22 Apr 2024
DOIs	https://doi.org/10.3390/biomedicines12040927
Publication status	Published - Apr 2024

Keywords

Alzheimer’s disease
animal models
combined metabolic activators
Parkinson’s disease

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10.3390/biomedicines12040927Licence: CC BY

Combined Metabolic Activators with_ALTAY_Publishedonline22April2024_GOLD_VoR (CC BY)Final published version, 3.96 MBLicence: CC BY

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Altay, O., Yang, H., Yildirim, S., Bayram, C., Bolat, I., Oner, S., Tozlu, O. O., Arslan, M. E., Hacimuftuoglu, A., Shoaie, S., Zhang, C., Borén, J., Uhlén, M., Turkez, H., & Mardinoglu, A. (2024). Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases. Biomedicines, 12(4), Article 927. https://doi.org/10.3390/biomedicines12040927

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title = "Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases",

abstract = "Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson{\textquoteright}s disease (PD) and Alzheimer{\textquoteright}s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.",

keywords = "Alzheimer{\textquoteright}s disease, animal models, combined metabolic activators, Parkinson{\textquoteright}s disease",

author = "Ozlem Altay and Hong Yang and Serkan Yildirim and Cemil Bayram and Ismail Bolat and Sena Oner and Tozlu, {Ozlem Ozdemir} and Arslan, {Mehmet Enes} and Ahmet Hacimuftuoglu and Saeed Shoaie and Cheng Zhang and Jan Bor{\'e}n and Mathias Uhl{\'e}n and Hasan Turkez and Adil Mardinoglu",

note = "Publisher Copyright: {\textcopyright} 2024 by the authors.",

year = "2024",

month = apr,

doi = "10.3390/biomedicines12040927",

language = "English",

volume = "12",

journal = "Biomedicines",

issn = "2227-9059",

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number = "4",

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Altay, O, Yang, H, Yildirim, S, Bayram, C, Bolat, I, Oner, S, Tozlu, OO, Arslan, ME, Hacimuftuoglu, A, Shoaie, S , Zhang, C, Borén, J, Uhlén, M, Turkez, H & Mardinoglu, A 2024, 'Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases', Biomedicines, vol. 12, no. 4, 927. https://doi.org/10.3390/biomedicines12040927

TY - JOUR

T1 - Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases

AU - Altay, Ozlem

AU - Yang, Hong

AU - Yildirim, Serkan

AU - Bayram, Cemil

AU - Bolat, Ismail

AU - Oner, Sena

AU - Tozlu, Ozlem Ozdemir

AU - Arslan, Mehmet Enes

AU - Hacimuftuoglu, Ahmet

AU - Shoaie, Saeed

AU - Zhang, Cheng

AU - Borén, Jan

AU - Uhlén, Mathias

AU - Turkez, Hasan

AU - Mardinoglu, Adil

PY - 2024/4

Y1 - 2024/4

N2 - Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.

AB - Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.

KW - Alzheimer’s disease

KW - animal models

KW - combined metabolic activators

KW - Parkinson’s disease

UR - http://www.scopus.com/inward/record.url?scp=85191714229&partnerID=8YFLogxK

U2 - 10.3390/biomedicines12040927

DO - 10.3390/biomedicines12040927

M3 - Article

AN - SCOPUS:85191714229

SN - 2227-9059

VL - 12

JO - Biomedicines

JF - Biomedicines

IS - 4

M1 - 927

ER -

Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases

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