scholarly journals PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 861
Author(s):  
Masamichi Ikawa ◽  
Hidehiko Okazawa ◽  
Yasunari Nakamoto ◽  
Makoto Yoneda
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Pet Imaging ◽  
Neurodegenerative Disorders ◽  
Mitochondrial Respiratory Chain ◽  
Redox Status ◽  
Brain Regions ◽  
Promising Tool ◽  
Positron Emission ◽  
Lateral Sclerosis

Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission tomography (PET) can directly evaluate subtle biological changes, including the redox status. The present review focuses on recent advances in PET imaging for oxidative stress, in particular the use of the Cu-ATSM radioligand, in neurodegenerative disorders associated with mitochondrial dysfunction. Since reactive oxygen species are mostly generated by leakage of excess electrons from an over-reductive state due to mitochondrial respiratory chain impairment, PET with 62Cu-ATSM, the accumulation of which depends on an over-reductive state, is able to image oxidative stress. 62Cu-ATSM PET studies demonstrated enhanced oxidative stress in the disease-related brain regions of patients with mitochondrial disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, the magnitude of oxidative stress increased with disease severity, indicating that oxidative stress based on mitochondrial dysfunction contributes to promoting neurodegeneration in these diseases. Oxidative stress imaging has improved our insights into the pathological mechanisms of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant therapies.

scholarly journals The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 552
Author(s):  
Jasmine Harley ◽  
Benjamin E. Clarke ◽  
Rickie Patani
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Mitochondrial Dysfunction ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Therapeutic Strategies ◽  
Lateral Sclerosis

RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.

Mitochondrial Dysfunction in Aging and Neurodegeneration

2019 ◽  
pp. 76-101
Author(s):  
Vaibhav Walia ◽  
Munish Garg
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorders ◽  
Electron Transport Chain ◽  
Tricarboxylic Acid ◽  
Atp Production ◽  
Important Target ◽  
Transport Chain ◽  
Cellular Apoptosis

Mitochondria are a dynamic organelle of the cell involved in the various biological processes. Mitochondria are the site of the adenosine triphosphate (ATP) production, electron transport chain (ETC), oxidation of fatty acids, tricarboxylic acid (TCA), and cellular apoptosis. Besides these, mitochondria are the site of production of reactive oxygen species (ROS), which further disrupts the normal functioning of this organelle also making mitochondria itself as an important target of oxidative stress. Thus, mitochondria serve as an important target in the process of neurodegeneration. In the present chapter, the authors describe mitochondria and its functioning, dynamics, and the mitochondrial dysfunction in aging and neurodegenerative disorders (NDs).

scholarly journals [18F]-T807 tauopathy PET imaging in chronic traumatic encephalopathy

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 229 ◽  
Author(s):  
Sam Gandy ◽  
Steven T. DeKosky
Keyword(s):  
Pet Imaging ◽  
Brain Injuries ◽  
Chronic Traumatic Encephalopathy ◽  
Neurofibrillary Tangle ◽  
Brain Regions ◽  
Tracer Uptake ◽  
Positron Emission ◽  
Molecular Ligand ◽  
Mesial Temporal Lobe ◽  
Recent Case Report

A new molecular ligand for positron emission tomography (PET) of the human brain, [18F]-T807, is under investigation for the antemortem detection of pathological neurofibrillary aggregates, which are evidence of neurofibrillary tangle (NFT) diseases, also known as tauopathies. Repetitive mild traumatic brain injuries in athletes and battlefield veterans are associated with one such tauopathy, known as chronic traumatic encephalopathy (CTE). In a recent case report, a former NFL player with clinically probable CTE and a concurrent Progressive Supranuclear Palsy (PSP) –like syndrome was studied using [18F]-T807. The interpretation of this player’s [18F]-T807 PET imaging was complicated by the overlap of tracer uptake in brain regions involved in CTE and PSP with regions associated with either nonspecific [18F]-T807 ligand binding or “aging-associated” binding of [18F]-T807 to authentic tauopathy known to be associated with aging and disease severity (i.e., NFT in the mesial temporal lobe). The implications of these data for the utility of [18F]-T807 in the pre-mortem detection of CTE are summarized.

scholarly journals Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice

2019 ◽  
Vol 40 (6) ◽  
pp. 1351-1362 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jeroen Verhaeghe ◽  
Alan Miranda ◽  
Istvan Kertesz ◽  
Klaudia Cybulska ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Neurodegenerative Disorder ◽  
Input Function ◽  
Dependent Manner ◽  
In Vivo Metabolism ◽  
Promising Tool ◽  
Positron Emission ◽  
Synaptic Pathology

Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [11C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K1 (IDIF). A scan duration of 60 min was sufficient for reliable VT (IDIF) and K1 (IDIF) estimations. In vivo metabolism of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.

Mitochondria and Neurodegeneration

2007 ◽  
Vol 27 (1-3) ◽  
pp. 87-104 ◽  
Author(s):  
Lucia Petrozzi ◽  
Giulia Ricci ◽  
Noemi J. Giglioli ◽  
Gabriele Siciliano ◽  
Michelangelo Mancuso
Keyword(s):  
Alzheimer’S Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Huntington's Disease ◽  
Neurodegenerative Disorders ◽  
Molecular Abnormalities ◽  
Lateral Sclerosis ◽  
Lines Of Evidence

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question “is mitochondrial dysfunction a necessary step in neurodegeneration?” is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration.

Circadian disruption in mice through chronic jetlag-like conditions modulates molecular profiles of cancer in nucleus accumbens and prefrontal cortex

2021 ◽  
Author(s):  
Suliman Khan ◽  
V Wee Yong ◽  
Mengzhou Xue
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Pet Imaging ◽  
Biological Rhythms ◽  
Brain Regions ◽  
Molecular Signature ◽  
Environmental Light ◽  
Positron Emission ◽  
The Individual ◽  
Risk Of Cancer

Abstract Biological rhythms regulate physiological activities. Shiftwork disrupts normal circadian rhythms and may increase the risk of cancer through unknown mechanisms. To mimic environmental light/dark changes encountered by shift workers, a protocol called “chronic jet lag (CJL)” induced by repeatedly shifting light-dark cycles has been used. Here, we subjected mice to CJL by advancing light–dark cycle by 6 hours every 2 days, and conducted RNA sequencing to analyze the expression profile and molecular signature in the brain areas of prefrontal cortex and nucleus accumbens. We also performed positron emission tomography (PET) imaging to monitor changes related to glucose metabolism in brain. Our results reveal systematic reprogramming of gene expression associated with cancer related pathways and metabolic pathways in prefrontal cortex and nucleus accumbens. PET imaging indicates that glucose uptake level was significantly reduced in whole brain as well as the individual brain regions. Moreover, qPCR analysis describes that the expression levels of cancer related genes were altered in prefrontal cortex and nucleus accumbens. Overall, these results suggest a molecular and metabolic link with CJL mediated cancer risk, and generate hypotheses on how CJL increases the susceptibility to cancer.

scholarly journals Aging-Related Disorders and Mitochondrial Dysfunction: A Critical Review for Prospect Mitoprotective Strategies Based on Mitochondrial Nutrient Mixtures

2020 ◽  
Vol 21 (19) ◽  
pp. 7060
Author(s):  
Giovanni Pagano ◽  
Federico V. Pallardó ◽  
Alex Lyakhovich ◽  
Luca Tiano ◽  
Maria Rosa Fittipaldi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorders ◽  
Clinical Studies ◽  
Antioxidant Properties ◽  
Cardiovascular Disorders ◽  
Combined Administration

A number of aging-related disorders (ARD) have been related to oxidative stress (OS) and mitochondrial dysfunction (MDF) in a well-established body of literature. Most studies focused on cardiovascular disorders (CVD), type 2 diabetes (T2D), and neurodegenerative disorders. Counteracting OS and MDF has been envisaged to improve the clinical management of ARD, and major roles have been assigned to three mitochondrial cofactors, also termed mitochondrial nutrients (MNs), i.e., α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and carnitine (CARN). These cofactors exert essential–and distinct—roles in mitochondrial machineries, along with strong antioxidant properties. Clinical trials have mostly relied on the use of only one MN to ARD-affected patients as, e.g., in the case of CoQ10 in CVD, or of ALA in T2D, possibly with the addition of other antioxidants. Only a few clinical and pre-clinical studies reported on the administration of two MNs, with beneficial outcomes, while no available studies reported on the combined administration of three MNs. Based on the literature also from pre-clinical studies, the present review is to recommend the design of clinical trials based on combinations of the three MNs.

scholarly journals Vitamin E Prevents ΔN-Bcl-xL-associate Mitochondrial Dysfunction in Primary Hippocampal Neurons (P14-024-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Han-A Park ◽  
Nelli Mnatsakanyan ◽  
Katheryn Broman ◽  
Elizabeth Jonas
Keyword(s):  
Oxidative Stress ◽  
Vitamin E ◽  
Mitochondrial Dysfunction ◽  
Neuronal Death ◽  
Hippocampal Neurons ◽  
Synapse Formation ◽  
B Cell Lymphoma ◽  
Redox Status ◽  
Mitochondrial Potential ◽  
Primary Hippocampal Neurons

Abstract Objectives B-cell lymphoma-extra large (Bcl-xL) is a pro-survival protein localized to mitochondria. Bcl-xL is reported to support brain function by enhancing neuronal energy metabolism, synapse formation, and neurite outgrowth. However, under exposure to excitotoxic stimulation and subsequent oxidative stress, Bcl-xL undergoes caspase dependent cleavage to ∆N-Bcl-xL. Accumulation of ∆N-Bcl-xL is associated with neuronal death; thus, approaches that prevent ∆N-Bcl-xL accumulation protect neurons from excitotoxic insult. In this study, we hypothesize that ∆N-Bcl-xL formation is regulated by redox status in mitochondria. We thus tested if production of ∆N-Bcl-xL can be inhibited by the fat-soluble antioxidant α-tocotrienol (TCT) given its ability to scavenge free radicals produced in the mitochondrial membrane. Methods Primary hippocampal neurons were treated with α-TCT, glutamate, or a combination of both, and mitochondrial oxidative stress, mitochondrial potential, caspase activity, and ∆N-Bcl-xL protein levels were quantified. Results Glutamate caused abnormalities in mitochondrial function leading to neuronal death. The antioxidant α-TCT protected neurons from glutamate-induced mitochondrial dysfunction and cytotoxicity. α-TCT treatment protected against cleavage of full length anti-apoptotic Bcl-xL to form pro-death ∆N-Bcl-xL. α-TCT significantly attenuated glutamate-induced reactive oxygen species (ROS) formation, caspase 3 activation and ∆N-Bcl-xL formation at mitochondria. Conclusions Our data suggests that oxidative stress production during excitotoxicity is responsible for the formation of ∆N-Bcl-xL. Thus, application of a lipophilic antioxidant such as vitamin E is neuroprotective by improving mitochondrial redox status and preventing production of neurotoxic ∆N-Bcl-xL. Funding Sources -NINDS, RO1 -University of Alabama, RGC internal grant.

scholarly journals The Antiaggregative and Antiamyloidogenic Properties of Nanoparticles: A Promising Tool for the Treatment and Diagnostics of Neurodegenerative Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Monika Pichla ◽  
Grzegorz Bartosz ◽  
Izabela Sadowska-Bartosz
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
High Throughput ◽  
Diagnostic Tool ◽  
Neurodegenerative Disorders ◽  
High Throughput Screening ◽  
Promising Tool ◽  
Socioeconomic Burden ◽  
Lateral Sclerosis

Due to the progressive aging of the society, the prevalence and socioeconomic burden of neurodegenerative diseases are predicted to rise. The most common neurodegenerative disorders nowadays, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, can be classified as proteinopathies. They can be either synucleinopathies, amyloidopathies, tauopathies, or TDP-43-related proteinopathies; thus, nanoparticles with a potential ability to inhibit pathological protein aggregation and/or degrade already existing aggregates can be a promising approach in the treatment of neurodegenerative diseases. As it turns out, nanoparticles can be a double-edged sword; they can either promote or inhibit protein aggregation, depending on coating, shape, size, surface charge, and concentration. In this review, we aim to emphasize the need of a breakthrough in the treatment of neurodegenerative disorders and draw attention to nanomaterials, as they can also serve as a diagnostic tool for protein aggregates or can be used in a high-throughput screening for novel antiaggregative compounds.

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