Taxifolin Alleviates Metabolic and Neurochemical Alterations in Hippocampus and Cortex of Brain of Rotenone-Toxified Rats in Vivo and Effectively Interacts with Enzymes Involve in Neurotransmission in Silico

Abstract Rotenone is a naturally occurring compound and inhibitor of mitochondrial complex I. Its exposure is toxic and directly affects the function of mitochondrial which leads to neurodegeneration. Taxifolin is a flavonoid that exhibits therapeutic potentials in various neurodegenerative diseases via its anti-oxidative, anti-inflammatory and neuromodulatory properties. In this study, we evaluated the therapeutic potential of taxifolin to alleviate metabolic and neurochemical alterations in the hippocampal and cortical region of brain of rotenone-toxified rats in vivo and to assess its influence on some enzymes involve in neurotransmission in silico. Taxifolin (0.25, 0.5 and 1.0 mg/kg) was orally post-administered to male Wistar rats for 3 days after 10 days subcutaneous administration of rotenone. Activities of mitochondrial complex I, membrane ion pump and lactate dehydrogenase (LDH) were evaluated in the hippocampus and cortex of the brain of rotenone-toxified rats. Markers of neurotransmitter metabolism and oxidative stress were also biochemically estimated and molecular interaction between taxifolin and tyrosine hydroxylase, monoamine oxidase, glutamine synthetase and Na+K+ ATPase was determined by in silico simulation. Taxifolin attenuated dysfunction of mitochondrial, Na+K+ ATPase, LDH and modulate neurotransmitter metabolism. Also, the elicited oxidative stress was mitigated by taxifolin in the hippocampus and cortex of the brain of rotenone-toxified rats. The highest binding affinity was recorded in taxifolin and tyrosine hydroxylase complex. Hydrogen bond and hydrophobic interactions were the two key molecular interaction between the taxifolin and targeted enzymes. Thus, taxifolin significantly exert therapeutic effect against rotenone-induced neurotoxicity in rats via anti-oxidative, as well as mitochondrial and neurotransmitter modulatory activity.

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Effects of lithium treatment on oxidative stress markers in mitochondrial complex I and complex III inhibition and after CO2 exposure in SH-SY5Y cells

10.31487/j.nnb.2019.01.001 ◽

2019 ◽

Author(s):

Frederic Marmol

Keyword(s):

Oxidative Stress ◽

Complex I ◽

Lithium Treatment ◽

Complex Iii ◽

Mitochondrial Complex I ◽

Oxidative Stress Markers ◽

Mitochondrial Complex ◽

Stress Markers

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Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00448-1 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Tatsuhiro Terada ◽

Joseph Therriault ◽

Min Su Peter Kang ◽

Melissa Savard ◽

Tharick Ali Pascoal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Complex I ◽

Clinical Symptoms ◽

Mitochondrial Complex I ◽

Braak Stage ◽

Mitochondrial Complex ◽

Temporal Area

Abstract Background Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. Methods Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. Results The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. Conclusions Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

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In vivo induction of heat shock proteins in the substantia nigra following L-DOPA administration is associated with increased activity of mitochondrial complex I and nitrosative stress in rats: regulation by glutathione redox state

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2006.04367.x ◽

2007 ◽

Vol 101 (3) ◽

pp. 709-717 ◽

Cited By ~ 43

Author(s):

Vittorio Calabrese ◽

Cesare Mancuso ◽

Agrippino Ravagna ◽

Marzia Perluigi ◽

Chiara Cini ◽

...

Keyword(s):

Complex I ◽

Redox State ◽

Nitrosative Stress ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Shock Proteins ◽

Increased Activity ◽

Glutathione Redox ◽

In Vivo Induction

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Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2016.04.027 ◽

2016 ◽

Vol 96 ◽

pp. 190-198 ◽

Cited By ~ 29

Author(s):

Lise Mathieu ◽

Alexandra Lopes Costa ◽

Carole Le Bachelier ◽

Abdelhamid Slama ◽

Anne-Sophie Lebre ◽

...

Keyword(s):

Oxidative Stress ◽

Complex I ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Complex I Deficiency

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Molecular mechanism and physiological role of active–deactive transition of mitochondrial complex I

Biochemical Society Transactions ◽

10.1042/bst20130088 ◽

2013 ◽

Vol 41 (5) ◽

pp. 1325-1330 ◽

Cited By ~ 21

Author(s):

Marion Babot ◽

Alexander Galkin

Keyword(s):

Complex I ◽

Physiological Role ◽

Protective Mechanism ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

The Status ◽

Nitric Oxide Metabolites

The unique feature of mitochondrial complex I is the so-called A/D transition (active–deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone (k ~104 min−1) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow (k ~1–10 min−1) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys39 of mitochondrially encoded subunit ND3 makes the D-form susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation.

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Inhibition of Mitochondrial Complex I Aggravates Folic Acid-Induced Acute Kidney Injury

Kidney & Blood Pressure Research ◽

10.1159/000501934 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1002-1013 ◽

Cited By ~ 2

Author(s):

Wen Zhang ◽

Yunwen Yang ◽

Huiping Gao ◽

Yue Zhang ◽

Zhanjun Jia ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Folic Acid ◽

Mitochondrial Dysfunction ◽

Complex I ◽

Kidney Injury ◽

Mitochondrial Complex I ◽

Tubular Injury ◽

Mitochondrial Complex ◽

Renal Tubular

Background: Some researches revealed that mitochondrial dysfunction is associated with various kidney injury. However, the role of mitochondrial dysfunction in the pathogenesis of acute kidney injury (AKI) still needs evidence. Methods: We evaluated the effect of mitochondrial complex I inhibitor rotenone on folic acid (FA)-induced AKI in mice. Results: Strikingly, the mice pretreated with rotenone at a dose of 200 ppm in food showed exacerbated kidney injury as shown by higher levels of blood urea nitrogen and creatinine compared with FA alone group. Meanwhile, both renal tubular injury score and the expression of renal tubular injury marker neutrophil gelatinase-associated lipocalin were further elevated in rotenone-pretreated mice, suggesting the deteriorated renal tubular injury. Moreover, the decrements of mitochondrial DNA copy number and the expressions of mitochondrial Cytochrome c oxidase subunit 1, mitochondrial NADH dehydrogenase subunit 1, and mitochondria-specific superoxide dismutase (SOD2) in the kidneys of FA-treated mice were further reduced in rotenone-pretreated mice, indicating the aggravated mitochondrial damage. In parallel with the SOD2 reduction, the oxidative stress markers of malondialdehyde and HO-1 displayed greater increment in AKI mice with rotenone pretreatment in line with the deteriorated apoptotic response and inflammation. Conclusion: Our results suggested that the inhibition of mitochondrial complex I activity aggravated renal tubular injury, mitochondrial damage, oxidative stress, cell apoptosis, and inflammation in FA-induced AKI.

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