Abstract
Background
Alzheimer’s disease (AD) is a prominent cause of dementia, resulting in neurodegeneration and memory impairment. This condition imposes a considerable public health burden on both patients and their families due to the patients’ functional impairments as well as the psychological and financial constraints. It has been well demonstrated that its aetiology involves proteinopathy, mitochondriopathies, and enhanced reactive oxygen species (ROS) generation, which are some of the key features of AD brains that further result in oxidative stress, excitotoxicity, autophagy, and mitochondrial dysfunction.
Objective
The current investigation was created with the aim of elucidating the neurological defence mechanism of trans,trans-Farnesol (TF) against intracerebroventricular-streptozotocin (ICV-STZ)-induced Alzheimer-like symptoms and related pathologies in rodents.
Materials and methods
The current investigation involved male SD rats receiving TF (25–100 mg/kg, per oral) consecutively for 21 days in ICV-STZ-treated animals. An in silico study was carried out to explore the possible interaction between TF and NADH dehydrogenase and succinate dehydrogenase. Further, various behavioural (Morris water maze and novel object recognition test), biochemical (oxidants and anti-oxidant markers), activities of mitochondrial enzyme complexes and acetylcholinesterase (AChE), pro-inflammatory (tumor necrosis factor-alpha; TNF-α) levels, and histopathological studies were evaluated in specific brain regions.
Results
Rats administered ICV-STZ followed by treatment with TF (25, 50, and 100 mg/kg) for 21 days had significantly better mental performance (reduced escape latency to access platform, extended time spent in target quadrant, and improved differential index) in the Morris water maze test and new object recognition test models when compared to control (ICV-STZ)-treated groups. Further, TF treatment significantly restored redox proportion, anti-oxidant levels, regained mitochondrial capacities, attenuated altered AChE action, levels of TNF-α, and histopathological alterations in certain brain regions in comparison with control. In in silico analysis, TF caused greater interaction with NADH dehydrogenase and succinate dehydrogenase.
Conclusion
The current work demonstrates the neuroprotective ability of TF in an experimental model with AD-like pathologies. The study further suggests that the neuroprotective impacts of TF may be related to its effects on TNF-α levels, oxidative stress pathways, and mitochondrial complex capabilities.
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Data availability
Data will be made available on request.
Abbreviations
- 5XTC:
-
Cryo-EM structure of human respiratory complex I transmembrane arm
- 4YTP:
-
Crystal structure of porcine heart mitochondrial complex II bound with N-[(4-tert-butylphenyl)methyl]-2-(trifluoromethyl)benzamide
- AChE:
-
Acetylcholinesterase
- ACSF:
-
Artificial cerebrospinal fluid
- AD:
-
Alzheimer’s disease
- ANOVA:
-
Analysis of variance
- APP:
-
Amyloid-protein precursor
- ATP:
-
Adenosine triphosphate
- BSA:
-
Bovine serum albumin
- Bw:
-
Body weight
- CPCSEA:
-
Committee for purpose of control and supervision of experiments on animals
- DCFH-DA:
-
2′, 7′ -Dichlorofluorescin diacetate
- DG:
-
Dentate gyrus
- DPX:
-
Distrene plasticizer xylene
- EGTA:
-
Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- ELISA:
-
Enzyme-linked immunosorbent assay
- ETC:
-
Electron transport chain
- FAD:
-
Familial Alzheimer’s disease
- Gala:
-
Galantamine
- GSH:
-
Reduced glutathione
- H2O2:
-
Hydrogen peroxide
- HEPES:
-
(4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)
- IAEC:
-
Institutional Animal Ethics Committee
- ICV-STZ:
-
Intracerebroventricular-streptozotocin
- IL-6:
-
Interleukin-6
- KOH:
-
Potassium hydroxide solution
- LPO:
-
Lipid peroxidation
- MDA:
-
Malondialdehyde
- mtDNA:
-
Mitochondrial DNA
- MTT:
-
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-H-tetrazolium bromide
- MWM:
-
Morris water maze
- NADH:
-
Nicotinamide adenine dinucleotide
- NOR or NORT:
-
Novel object recognition test
- OH•:
-
Hydroxyl radicals
- ONOO− :
-
Peroxynitrite
- OXPHOS:
-
Oxidative phosphorylation
- PLIP:
-
Protein–Ligand Interaction Profiler
- PMS:
-
Post mitochondrial supernatant
- PNS:
-
Post nuclear supernatant
- PS 1 or 2:
-
Presenilin 1 or 2
- RNS:
-
Reactive nitrogen species
- ROS:
-
Reactive oxygen species
- SAD:
-
Sporadic Alzheimer’s disease
- SD:
-
Sprague–Dawley
- SDH:
-
Succinate dehydrogenase
- SEM:
-
Standard error of the mean
- SOD:
-
Superoxide dismutase
- TBA:
-
Thiobarbituric acid
- TBARS:
-
Thiobarbituric-acid reactive substance
- TF:
-
Trans,trans-Farnesol
- TNF-α:
-
Tumor necrosis factor- alpha
- TSTQ:
-
Time spent in target quadrant
- UV–Vis:
-
Ultraviolet–visible
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Acknowledgements
We sincerely appreciate the help provided by the ICMR-SRF and RA grants (No. 45/35/2018-PHA/BMS and 3/1/3/5/M/2022-NCD-II) from the Indian Council of Medical Research (ICMR), New Delhi, India.
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MK: design and creation of the research; planning, and executing behavioral investigations; carrying out the surgery; assessing the outcomes; performing outcomes analysis; and writing the manuscript. NS: executing experiments (ROS and protein carbonyls estimation), evaluating the results, statistical analysis. AK: carrying out experiments (ROS, protein carbonyls and TNF-alpha estimation), evaluating the results. AK: design and creation of the research; creating and directing all of the experiments; evaluating and analysing the results; writing, reviewing, and editing the manuscript.
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Kadian, M., Saini, N., Khera, A. et al. Neuroprotective mechanism of trans,trans-Farnesol in an ICV-STZ-induced rat model of Alzheimer’s pathology. Inflammopharmacol 32, 1545–1573 (2024). https://doi.org/10.1007/s10787-023-01413-8
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DOI: https://doi.org/10.1007/s10787-023-01413-8