Imaging of Superoxide Generation in the Dopaminergic Area of the Brain in Parkinson’s Disease, Using Mito-TEMPO

Zhelev, Zhivko; Bakalova, Rumiana; Aoki, Ichio; Lazarova, Dessislava; Saga, Tsuneo

doi:10.1021/cn400159h

Cited by 49 publications

(62 citation statements)

References 29 publications

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“…686,687 Mito-TEMPO was used to monitor the redox status of the dopaminergic sector of the brain in the MPTP-based mouse model of PD. 687 A weak and short-lived nitroxide-enhanced signal was observed in the brain of healthy animals.…”

Section: Mitochondria-targeted Agents In Imagingmentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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Section: Mitochondria-targeted Agents In Imagingmentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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“…In this context, high superoxide concentrations have been observed in familial ALS, which is caused by mutations in the gene encoding CuZnSOD (SOD1) (Andersen 2004). Augmented superoxide levels have also been demonstrated in the dopaminergic area of individuals affected by PD (Zhelev et al 2013). Furthermore, β-amyloid peptides, which aggregate in the senile plaques characteristic of AD, have been shown to induce the generation of superoxide mediated by NADPH oxidase activation (Parajuli et al 2013) and hydroxyl radicals through the Fenton reaction (Rival et al 2009;La Penna et al 2013).…”

Section: Disruption Of Redox Homeostasis Is Involved In Common Neurolmentioning

confidence: 99%

Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

Leipnitz

Vargas

Wajner

2015

J of Inher Metab Disea

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3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is an inherited disorder of organic acid metabolism biochemically characterized by tissue accumulation and high urinary excretion of 3-hydroxy-3-methylgutarate, 3-methylglutarate, 3-methylglutaconate and 3-hydroxyisovalerate. Affected patients predominantly present neurological symptoms that are accompanied by mild hepatopathy during episodes of catabolic crisis. The pathophysiology of this disease is poorly known, although recent animal and human in vitro and in vivo studies have suggested that oxidative stress caused by the major accumulating organic acids may represent a pathomechanism of brain and liver damage in HL deficiency. In this review we focus on the deleterious effects of these carboxylic acids on redox homeostasis in rat and human tissues that may offer new perspectives for potential novel adjuvant therapeutic strategies in this disorder.

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“…In addition, animal models of PD using agents such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine have demonstrated increased production of superoxide in dopaminergic cells relative to cortex [120]. Furthermore, mitochondrial localization of α-synuclein has been shown to promote oxidative stress in vitro [121].…”

Section: Pathological Mechanisms Of Neurodegenerative Diseasesmentioning

confidence: 99%

Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases

Cruz-Haces

Tang

Acosta

et al. 2017

Transl Neurodegener

126

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Traumatic brain injury is among the most common causes of death and disability in youth and young adults. In addition to the acute risk of morbidity with moderate to severe injuries, traumatic brain injury is associated with a number of chronic neurological and neuropsychiatric sequelae including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. However, despite the high incidence of traumatic brain injuries and the established clinical correlation with neurodegeneration, the causative factors linking these processes have not yet been fully elucidated. Apart from removal from activity, few, if any prophylactic treatments against post-traumatic brain injury neurodegeneration exist. Therefore, it is imperative to understand the pathophysiological mechanisms of traumatic brain injury and neurodegeneration in order to identify potential factors that initiate neurodegenerative processes. Oxidative stress, neuroinflammation, and glutamatergic excitotoxicity have previously been implicated in both secondary brain injury and neurodegeneration. In particular, reactive oxygen species appear to be key in mediating molecular insult in neuroinflammation and excitotoxicity. As such, it is likely that post injury oxidative stress is a key mechanism which links traumatic brain injury to increased risk of neurodegeneration. Consequently, reactive oxygen species and their subsequent byproducts may serve as novel fluid markers for identification and monitoring of cellular damage. Furthermore, these reactive species may further serve as a suitable therapeutic target to reduce the risk of post-injury neurodegeneration and provide long term quality of life improvements for those suffering from traumatic brain injury.

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Imaging of Superoxide Generation in the Dopaminergic Area of the Brain in Parkinson’s Disease, Using Mito-TEMPO

Cited by 49 publications

References 29 publications

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases

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