N-Methyl, N-propynyl-2-phenylethylamine (MPPE), a Selegiline Analog, Attenuates MPTP-induced Dopaminergic Toxicity with Guaranteed Behavioral Safety: Involvement of Inhibitions of Mitochondrial Oxidative Burdens and p53 Gene-elicited Pro-apoptotic Change

Shin, Eun‐Joo; Nam, Yunsung; Lee, Ji Won; Nguyen, Phuong-Khue Thi; Yoo, Ji Eun; Tran, The-Vinh; Jeong, Ji Hoon; Jang, Choon‐Gon; Oh, Young J.; Youdim, Moussa B. H.; Lee, Phil Ho; Nabeshima, Toshitaka; Kim, Hyoung‐Chun

doi:10.1007/s12035-015-9527-1

Cited by 36 publications

(22 citation statements)

References 94 publications

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“…In this model, PFT-μ administration prevented cognitive impairment and sensorimotor dysfunction associated with HI-induced brain apoptosis and structural damage (Nijboer et al, 2011). In addition, results from a recent study in a Parkinson's mouse model showed that PFT-μ prevents 1-methyl-4-phenyl-1, 2, 3, 6-thetrahydropyridine (MPTP)-induced neurotoxicity by inhibiting mitochondrial p53/Bcl-XL interactions, impaired mitochondrial transmembrane potential, and cytosolic cytochrome c release (Shin et al, 2016). Several studies using dissociated DRG neurons demonstrate that ex vivo incubation with cisplatin activates an apoptotic pathway as shown by Tunel staining, along with cytochrome c release and increase of reactive oxygen species production (McDonald and Windebank, 2002; Jiang et al, 2008; Melli et al, 2008; Florea and Busselberg, 2011).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Mitochondrial p53 Accumulation by PFT-μ Prevents Cisplatin-Induced Peripheral Neuropathy

Maj

Krukowski

et al. 2017

Front. Mol. Neurosci.

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Chemotherapy-induced peripheral neuropathy (CIPN), a debilitating major side effect of cancer treatment, is characterized by pain and sensory loss in hand and feet. Platinum-based chemotherapeutics like cisplatin frequently induce CIPN. The molecular mechanism underlying these neurotoxic symptoms is incompletely understood and there are no preventive or curative interventions. We hypothesized that cisplatin acts as a cellular stressor that triggers p53 accumulation at mitochondria, leading to mitochondrial dysfunction and CIPN. To test this hypothesis, we examined the effect of the small molecule pifithrin-μ (PFT-μ), an inhibitor of p53 mitochondrial association on CIPN and the associated mitochondrial dysfunction. We show here for the first time that in vivo cisplatin rapidly increases mitochondrial accumulation of p53 in dorsal root ganglia (DRG), spinal cord, and peripheral nerve without evidence for apoptosis. Cisplatin-treatment also reduced mitochondrial membrane potential and lead to abnormal mitochondrial morphology and impaired mitochondrial function in DRG neurons. Pre-treatment with PFT-μ prevented the early cisplatin-induced increase in mitochondrial p53 and the reduction in mitochondrial membrane potential. Inhibition of the early mitochondrial p53 accumulation by PFT-μ also prevented the abnormalities in mitochondrial morphology and mitochondrial bioenergetics (reduced oxygen consumption rate, maximum respiratory capacity, and adenosine triphosphate synthesis) that develop in DRG and peripheral nerve after cisplatin-treatment. Functionally, inhibition of mitochondrial p53 accumulation prevented the hallmarks of CIPN including mechanical allodynia, peripheral sensory loss (numbness) as quantified by an adhesive-removal task, and loss of intra-epidermal nerve fibers. In conclusion, PFT-μ is a potential neuroprotective agent that prevents cisplatin-induced mitochondrial dysfunction in DRG and peripheral nerves thereby protecting against CIPN through blockade of the early cisplatin-induced increase in mitochondrial p53. Notably, there is accumulating evidence that PFT-μ has anti-tumor activities and could therefore be an attractive candidate to prevent CIPN while promoting tumor cell death.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Mitochondrial p53 Accumulation by PFT-μ Prevents Cisplatin-Induced Peripheral Neuropathy

Maj

Krukowski

et al. 2017

Front. Mol. Neurosci.

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“…Mitochondria were isolated as described previously (Shin et al, ) with minor modifications (Shin et al, ). The animals were anesthetized with sodium pentobarbital (60 mg kg −1 ) and perfused transcardially with 30 ml ice‐cold homogenization buffer (250 m m sucrose, 20 m m HEPES, 1 m m EDTA, pH 7.2).…”

Section: Methodsmentioning

confidence: 99%

Protective potential of glutathione peroxidase‐1 gene against cocaine‐induced acute hepatotoxic consequences in mice

Nhu

Jung

Kim

et al. 2018

J of Applied Toxicology

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Since the cocaine-induced oxidative stress has been established to lead to hepatotoxicity, we examined the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced hepatotoxicity. Cocaine treatment significantly increased superoxide dismutase activity in as little as 1 hour, with a maximum level at 6 hours in wild-type mice, while significantly decreasing GPx activity and subsequently inducing oxidative damage (i.e., reactive oxygen species, lipid peroxidation and protein carbonylation). These changes were more prominent in the mitochondrial fraction than in the cytosolic fraction. In contrast, genetic overexpression of GPx-1 significantly attenuated cocaine-induced oxidative damage in mice. Cocaine treatment significantly increased alanine aminotransferase and aspartate aminotransferase levels in the serum. Consistently, cocaine significantly enhanced cleaved caspase-3 expression and intramitochondrial Ca , while significantly reducing mitochondrial transmembrane potential. Cocaine treatment potentiated cleavage of protein kinase C δ (PKCδ), mitochondrial translocation of PKCδ, cytosolic release of cytochrome c and activation of caspase-3, followed by hepatopathologic changes. These results were more prominent in GPx-1 knockout than in wild-type mice, and they were less pronounced in overexpressing transgenic than in non-transgenic mice. Combined, our results suggest that the GPx-1 gene possesses protective potential against mitochondrial oxidative burden, mitochondrial dysfunction and hepatic degeneration induced by cocaine and that the protective mechanisms are associated with anti-apoptotic activity via inactivation of PKCδ.

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“…GPx activity was analyzed by a spectrophotometric assay described by Lawrence and Burk, using 2.0 mM reduced glutathione and 0.25 mM cumene hydroperoxide as substrates . The reaction rate at 340 nm was determined using the NADPH extinction coefficient (6.22 mM −1 ⋅cm −1 ).…”

Section: Methodsmentioning

confidence: 99%

Glutathione peroxidase‐1 overexpressing transgenic mice are protected from neurotoxicity induced by microcystin‐leucine‐arginine

Shin

Hwang

Pham

et al. 2018

Environmental Toxicology

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Although it has been well-recognized that microcystin-leucine-arginine (MCLR), the most common form of microcystins, induces neurotoxicity, little is currently known about the underlying mechanism for this neurotoxicity. Here, we found that MCLR (10 ng/μL/mouse, i.c.v.) induces significant neuronal loss in the hippocampus of mice. MCLR-induced neurotoxicity was accompanied by oxidative stress, as shown by a significant increase in the level of 4-hydroxynonenal, protein carbonyl, and reactive oxygen species (ROS). Superoxide dismutase-1 (SOD-1) activity was significantly increased, but glutathione peroxidase (GPx) level was significantly decreased following MCLR insult. In addition, MCLR significantly inhibited GSH/GSSG ratio, and significantly induced NFκB DNA binding activity. Because reduced activity of GPx appeared to be critical for the imbalance between activities of SODs and GPx, we utilized GPx-1 overexpressing transgenic mice to ascertain the role of GPx-1 in this neurotoxicity. Genetic overexpression of GPx-1 or NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly attenuated MCLR-induced hippocampal neuronal loss in mice. However, PDTC did not exert any additive effect on neuroprotection mediated by GPx-1 overexpression, indicating that NFκB is a neurotoxic target of MCLR. Combined, these results suggest that MCLR-induced neurotoxicity requires oxidative stress associated with failure in compensatory induction of GPx, possibly through activation of the transcription factor NFκB.

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N-Methyl, N-propynyl-2-phenylethylamine (MPPE), a Selegiline Analog, Attenuates MPTP-induced Dopaminergic Toxicity with Guaranteed Behavioral Safety: Involvement of Inhibitions of Mitochondrial Oxidative Burdens and p53 Gene-elicited Pro-apoptotic Change

Cited by 36 publications

References 94 publications

Inhibition of Mitochondrial p53 Accumulation by PFT-μ Prevents Cisplatin-Induced Peripheral Neuropathy

Inhibition of Mitochondrial p53 Accumulation by PFT-μ Prevents Cisplatin-Induced Peripheral Neuropathy

Protective potential of glutathione peroxidase‐1 gene against cocaine‐induced acute hepatotoxic consequences in mice

Glutathione peroxidase‐1 overexpressing transgenic mice are protected from neurotoxicity induced by microcystin‐leucine‐arginine

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