RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

Türkez, Hasan; Altay, Özlem; Yıldırım, Serkan; Li, Xiangyu; Yang, Hong; Bayram, Cemil; Bolat, İsmail; Öner, Sena; Tozlu, Özlem Özdemir; Arslan, Mehmet; Arif, Muhammad; Yuluğ, Burak; Hanoğlu, Lütfü; Çankaya, Şeyda; Lam, Simon; Coşkun, Ebru; İdil, Ezgi; Nogaylar, Rahim; Özşimşek, Ahmet; Hacımüftüoğlu, Ahmet; Shoaie, Saeed; Zhang, Cheng; Nielsen, Jens; Borén, Jan; Uhlén, Mathias; Mardinoğlu, Adil

doi:10.1016/j.lfs.2022.121325

Cited by 8 publications

(15 citation statements)

References 90 publications

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“…The clinical results were consistent with the genome-scale metabolic modelling of more than 600 AD patients showing clear evidence of mitochondrial dysfunction [40]. It is also consistent with the results from an animal model demonstrating improvement in AD-associated histological parameters in animals treated with oral administration of CMA [67]. Thus, the present study suggests a promising therapeutic regime that might help to improve metabolic alterations in AD patients.…”

Section: Discussionsupporting

confidence: 89%

“…The effect of oral administration of CMA was substantiated with a comprehensive analysis of proteins and metabolites in the plasma of patients using a multi-omics analytical platform. The clinical results were consistent with the genome-scale metabolic modelling of more than 600 AD patients showing clear evidence of mitochondrial dysfunction [40]. It is also consistent with the results from an animal model demonstrating improvement in AD-associated histological parameters in animals treated with oral administration of CMA [67].…”

Section: Discussionsupporting

confidence: 85%

“…Moreover, plasma levels of metabolites associated with antioxidant metabolism and inflammation are improved in COVID-19 patients treated with CMA compared to the placebo [38]. Recently, we tested the individual metabolic activators and CMA in the streptozotocin-induced AD-like rats and showed that CMA administration significantly improved behavioural scores in parallel with neurohistological outcomes in this model [40].…”

Section: Discussionmentioning

confidence: 99%

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Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial

Yuluğ

Altay

et al. 2023

Transl Neurodegener

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Background Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial

Yuluğ

Altay

et al. 2023

Transl Neurodegener

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“…Future therapeutic strategies can focus on reprogramming metabolic pathways harnessing the beneficial effects of obesity while avoiding its detrimental consequences. Metabolic reprogramming has been experimented both preclinically and in clinical trials: In streptozotocin-induced AD-like female rats, a panel of orally administered metabolic activators yielded beneficial effects on neurodegeneration (Turkez et al, 2023). The same metabolic activators also improved cognitive readouts in a Phase II clinical trial consisting of 69 AD patients (Yulug et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Obesity Facilitates Sex-Specific Improvement In Cognition And Neuronal Function In A Rat Model Of Alzheimer’s Disease

Lai,

Almanza,

Ribeiro

et al. 2024

Preprint

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Obesity reduces or increases the risk of developing Alzheimer's disease (AD) depending on whether it is assessed in mid-life or late-life. There is currently no consensus on the relationship between obesity and AD or the mechanism or their interaction. Here, we aim to differentiate the cause-and-effect relationship between obesity and AD in a controlled rat model of AD. We induced obesity in 9-month-old TgF344-AD rats, that is pathology-load wise similar to early symptomatic phase of human AD. To more accurately model human obesity, we fed both TgF344-AD and non-transgenic littermates a varied high-carbohydrate-high-fat diet consisting of human food for 3 months. Obesity increased overall glucose metabolism and slowed cognitive decline in TgF344-AD rats, specifically executive function, without affecting non-transgenic rats. Pathological analyses of prefrontal cortex and hippocampus showed that obesity in TgF344-AD rats produced varied effects, with increased density of myelin and oligodendrocytes, lowered density and activation of microglia that we propose contributes to the cognitive improvement. However, obesity also decreased neuronal density, and promoted deposition of amyloid-beta plaques and tau inclusions. After 6 months on the high-carbohydrate-high-fat diet, detrimental effects on density of neurons, amyloid-beta plaques, and tau inclusions persisted while the beneficial effects on myelin, microglia, and cognitive functions remained albeit with a lower effect size. By examining the effect of sex, we found that both beneficial and detrimental effects of obesity were stronger in female TgF344-AD rats indicating that obesity during early symptomatic phase of AD is protective in females.

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“…Moreover, we have developed the combined metabolic activators (CMAs), consisting of L-carnitine tartrate, GSH precursors (L-serine and N-Acetyl Cysteine) and NAD+ precursor (Nicotinamide or Nicotinamide Riboside), to increase the level of NAD+ as well as GSH levels [ 57 , 58 ]. We tested the effect of the CMAs in the animal models of NDD and found that CMA can be used in decreasing oxidative stress and activating mitochondria, and eventually reversing the disease-associated phenotypes in the animals [ 59 ]. We also tested the effect of the CMA in PD patients [ 58 ] and Alzheimer’s Disease patients [ 60 ], and found that the cognitive function of the AD and PD patients significantly improved in these two independent placebo-controlled studies.…”

Section: Discussionmentioning

confidence: 99%

Costunolide and Parthenolide Ameliorate MPP+ Induced Apoptosis in the Cellular Parkinson’s Disease Model

Arslan

Türkez

Sevim

et al. 2023

Cells

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Monoamine oxidase B (MAO-B) is an enzyme that metabolizes several chemicals, including dopamine. MAO-B inhibitors are used in the treatment of Parkinson’s Disease (PD), and the inhibition of this enzyme reduces dopamine turnover and oxidative stress. The absence of dopamine results in PD pathogenesis originating from decreased Acetylcholinesterase (AChE) activity and elevated oxidative stress. Here, we performed a molecular docking analysis for the potential use of costunolide and parthenolide terpenoids as potential MAO-B inhibitors in the treatment of PD. Neuroprotective properties of plant-originated costunolide and parthenolide terpenoids were investigated in a cellular PD model that was developed by using MPP+ toxicity. We investigated neuroprotection mechanisms through the analysis of oxidative stress parameters, acetylcholinesterase activity and apoptotic cell death ratios. Our results showed that 100 µg/mL and 50 µg/mL of costunolide, and 50 µg/mL of parthenolide applied to the cellular disease model ameliorated the cytotoxicity caused by MPP+ exposure. We found that acetylcholinesterase activity assays exhibited that terpenoids could ameliorate and restore the enzyme activity as in negative control levels. The oxidative stress parameter analyses revealed that terpenoid application could enhance antioxidant levels and decrease oxidative stress in the cultures. In conclusion, we reported that these two terpenoid molecules could be used in the development of efficient treatment strategies for PD patients.

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RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

Cited by 8 publications

References 90 publications

Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial

Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial

Obesity Facilitates Sex-Specific Improvement In Cognition And Neuronal Function In A Rat Model Of Alzheimer’s Disease

Costunolide and Parthenolide Ameliorate MPP+ Induced Apoptosis in the Cellular Parkinson’s Disease Model

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