Potential of protease inhibitor in 3-nitropropionic acid induced Huntington's disease like symptoms: Mitochondrial dysfunction and neurodegeneration

Hariharan, Ashwini; Shetty, Shruthi R; Shirole, Trupti; Jagtap, Aarti

doi:10.1016/j.neuro.2014.10.004

Cited by 43 publications

(23 citation statements)

References 46 publications

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“…On the other hand, the observed decrease in SDHA and aconitase 2 content is in agreement with a number of HD studies, e.g., the decrease in SDHA and SDHB subunits in striatal patients' neurons [49] and also with studies mimicking HD by 3-nitropropionate treatment (complex II inhibitor) [50,51,52,53]. These studies propose that SDHB is particularly vulnerable to oxidative stress in HD because of the presence of Fe-S clusters in its structure.…”

Section: Discussionsupporting

confidence: 90%

Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs

Křížová

Stufkova²,

Rodinová³

et al. 2017

Neurodegener Dis

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Background: Huntington disease (HD) is a fatal neurodegenerative disorder involving reduced muscle coordination, mental and behavioral changes, and testicular degeneration. In order to further clarify the decreased fertility and penetration ability of the spermatozoa of transgenic HD minipig boars (TgHD), we applied a set of mitochondrial metabolism (MM) parameter measurements to this promising biological material, which can be collected noninvasively in longitudinal studies. Objective: We aimed to optimize methods for MM measurements in spermatozoa and to establish possible biomarkers of HD in TgHD spermatozoa expressing the N-terminal part of mutated human huntingtin. Methods: Semen samples from 12 TgHD and wild-type animals, aged 12-65 months, were obtained repeatedly during the study. Respiration was measured by polarography, MM was assessed by the detection of oxidation of radiolabeled substrates (mitochondrial energy-generating system; MEGS), and the content of the oxidative phosphorylation system subunits was detected by Western blot. Three possibly interfering factors were statistically analyzed: the effect of HD, generation and aging. Results: We found 5 MM parameters which were significantly diminished in TgHD spermatozoa and propose 3 specific MEGS incubations and complex I-dependent respiration as potential biomarkers of HD in TgHD spermatozoa. Conclusions: Our results suggest a link between the gain of toxic function of mutated huntingtin in TgHD spermatozoa and the observed MM and/or glycolytic impairment. We determined 4 biomarkers useful for HD phenotyping and experimental therapy monitoring studies in TgHD minipigs.

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Section: Discussionsupporting

confidence: 90%

Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs

Křížová

Stufkova²,

Rodinová³

et al. 2017

Neurodegener Dis

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“…ROS in turn renders mitochondria susceptible to oxidative damage. Mitochondrial dysfunction caused by ROS-induced oxidative damage has been shown to involve in the development of apoptotic cell death in HD as well as in 3-NP toxicity [10,11].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective efficacy of naringin on 3-nitropropionic acid-induced mitochondrial dysfunction through the modulation of Nrf2 signaling pathway in PC12 cells

Gopinath

Sudhandiran

2015

Mol Cell Biochem

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“…IL-6, TNF-α)[64,65]. A plethora of evidences shows that 3-NP chronically administrated in rodents and primates can replicate key abnormalities underlying HD pathogenesis, including molecular alterations dependent of mitochondrial dysfunction (energetic deficit, oxidant species accumulation) as well as clinical (motor and cognitive) signs[61,63,66,67] supporting the potential utility of the 3-NP intoxication model in HD studies[68,69].To analyze the neuroprotective and immune actions exerted by compound 8, we used the 3-NP intoxication model (as described in the experimental section). Mice were given increasing amounts of the toxin accompanied by the administration of compound 8 or resveratrol 1 which was used as reference.M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTEvaluation of the activity of compound 8 in a 3-NP-induced neurodegeneration animal model.…”

mentioning

confidence: 99%

Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases

Peñalver

Belmonte-Reche

Adán

et al. 2018

European Journal of Medicinal Chemistry

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Resveratrol is a naturally occurring stilbene which has shown promising results as treatment for several neurodegenerative diseases. However, its application is limited due to its low efficacy and bioavailability. Here, we have designed and synthesized alkylated resveratrol prodrugs combining structural modification to improve antioxidant and anti-inflammatory properties and the preparation of prodrugs to extend drug bioavailability. For comparison we also studied resveratrol prodrugs and alkylated resveratrol derivatives. Methylated and butylated resveratrol derivatives showed the best in vitro neuroprotective and anti-inflammatory activity. The glucosyl- and glucosyl-acyl- prodrugs of these derivatives showed lower toxicity on zebra fish embryo. When neuroprotection was examined on pentylenetetrazole challenged zebra fish, they were capable of reverting neuronal damage but to a lower extent than resveratrol. Nevertheless, 3-O-(6'-O-octanoyl)-β-d-glucopyranoside resveratrol (compound 8) recovered AChE activity over 100% whereas resveratrol only up to 92%. In a 3-nitropropionic acid mice model of Huntington's disease, resveratrol derivative 8 delayed the onset and reduced the severity of HD-like symptoms, by improving locomotor activity and protecting against weight loss. Its effects involved an equal antioxidant but better anti-inflammatory profile than resveratrol as shown by SOD2 expression in brain tissue and circulating levels of IL-6 (11 vs 18 pg/mL), respectively. Finally, the octanoyl chain in compound 8 could be playing a role in inflammation and neuronal development indicating it could be acting as a double-drug, instead of as a prodrug.

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Potential of protease inhibitor in 3-nitropropionic acid induced Huntington's disease like symptoms: Mitochondrial dysfunction and neurodegeneration

Cited by 43 publications

References 46 publications

Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs

Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs

Neuroprotective efficacy of naringin on 3-nitropropionic acid-induced mitochondrial dysfunction through the modulation of Nrf2 signaling pathway in PC12 cells

Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases

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