Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases
Journal article, 2023
Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.
Animal model
Combined metabolic activators
Neurodegenerative diseases
Genome-scale metabolic model
Author
Hasan Turkez
Atatürk University
Ozlem Altay
Royal Institute of Technology (KTH)
Serkan Yıldırım
Atatürk University
Xiangyu Li
Royal Institute of Technology (KTH)
Hong Yang
Royal Institute of Technology (KTH)
Cemil Bayram
Atatürk University
Ismail Bolat
Atatürk University
Sena Oner
Erzurum Technical University
Özlem Özdemir Tozlu
Erzurum Technical University
Mehmet Enes Arslan
Erzurum Technical University
Muhammad Arif
Royal Institute of Technology (KTH)
Burak Yulug
Alanya Alaaddin Keykubat University
Lutfu Hanoglu
Istanbul Medipol Universitesi
Seyda Cankaya
Alanya Alaaddin Keykubat University
Simon Lam
King's College London
Halil Aziz Velioglu
Istanbul Medipol Universitesi
Karolinska Institutet
Ebru Coskun
Istanbul Medipol Universitesi
Ezgi Idil
Alanya Alaaddin Keykubat University
Rahim Nogaylar
Alanya Alaaddin Keykubat University
Ahmet Ozsimsek
Alanya Alaaddin Keykubat University
Ahmet Hacımuftuoglu
Atatürk University
Saeed Shoaie
Royal Institute of Technology (KTH)
King's College London
C. Zhang
Zhengzhou University
Royal Institute of Technology (KTH)
Jens B Nielsen
Chalmers, Life Sciences, Systems and Synthetic Biology
Jan Borén
University of Gothenburg
Mathias Uhlen
Royal Institute of Technology (KTH)
Adil Mardinoglu
Royal Institute of Technology (KTH)
King's College London
Life Sciences
0024-3205 (ISSN) 18790631 (eISSN)
Vol. 314 121325Subject Categories
Pharmaceutical Sciences
Neurosciences
Neurology
DOI
10.1016/j.lfs.2022.121325
PubMed
36581096