3-Nitropropionic acid induces cell death and mitochondrial dysfunction in rat corticostriatal slice cultures

Vis, José C; Huizen, Roelie T. de Boer-van; Verbeek, Marcel M.; Waal, R. M. W. De; Donkelaar, Hans J. ten; Kremer, Berry

doi:10.1016/s0304-3940(02)00581-5

Cited by 18 publications

(19 citation statements)

References 21 publications

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“…The balance between the two types of cell death depends mainly on the severity of ATP depletion (Eguchi et al, 1997;Leist et al, 1997;Ohgoh et al, 2000) which is closely related with the dose and time of exposure to this toxin. In general, low doses of 3-NP induce less damage and an apoptotic-like cell death, while higher doses result in acute injury and necrosis (Vis et al, 2002). Our results showed that low doses of 3-NP (b1 mM) activate caspase-3 and lead to DNA fragmentation, without affecting plasma membrane integrity, which is in agreement with the occurrence of an apoptotic process.…”

Section: Discussionsupporting

confidence: 85%

“…Under these conditions, caspase activity is not affected, which is in agreement with cells undergoing death by necrosis (Nasr et al, 2003). On the other hand, apoptotic cell death induced by 3-NP has been largely documented through the analysis of DNA fragmentation by TUNEL staining, the release of cytochrome c, the activation of caspase-3, and alterations in the levels of the apoptosis-related protein markers Bax and Bcl-2 (Kim and Chan, 2001;Rodrigues et al, 2000;Vis et al, 2002).…”

Section: Introductionmentioning

confidence: 58%

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FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Almeida

Domingues

Rodrigues

et al. 2004

Neurobiology of Disease

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The mitochondrial toxin 3-nitropropionic acid (3-NP) has been largely used to study neurodegenerative disorders in which bioenergetic defects are implicated. In the present study, we analyzed the molecular pathways involved in FK506 neuroprotection against cell death induced by 3-NP, using cultured cortical neurons. 3-NP induced cytochrome c release and increased caspases -2, -3, -8, and -9-like activities, although, calpain activity was not significantly affected. FK506 decreased cytochrome c release and caspase-3-like activity induced by 3-NP, without changing the activities of other caspases. FK-506 also decreased the number of apoptotic neurons, determined by Hoechst. Under these conditions, FK506 alone significantly reduced calcineurin activity by about 50%. Our results also showed a decrease in mitochondrial Bax and an increase in mitochondrial Bcl-2 levels upon exposure to FK506 and 3-NP. However, no significant changes occurred in total Bcl-2 and Bax levels. Altogether, the results suggest that FK506 neuroprotection against 3-NP-induced apoptosis is associated with the redistribution of Bcl-2 and Bax in the mitochondrial membrane. D

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 58%

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Almeida

Domingues

Rodrigues

et al. 2004

Neurobiology of Disease

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“…In agreement with a previous report, 4 the present study observed robust DNA smear and DNA fragments of typical internucleosomal cleavage after infusion of 3-NP (125-500 nmol), indicating a mixed form of cell death (data not shown). To observe the time-course of 3-NP-induced autophagy activation, rats were infused with 3-NP (300 nmol) or vehicle (normal saline, 1 μl) and killed 1, 2, 4, 12, and 24 h later and the formation of autophagosomes and morphologic changes of cellular organelles were examined with transmission electron microscope (TEM).…”

Section: -Np Induced Autophagy Activationsupporting

confidence: 94%

“…1,2 One generally recognized scenario accounting for 3-NP-induced striatal degeneration is that depletion in ATP levels, produced by a deficit in energy metabolism, can lead to membrane depolarization and produce glutamate toxicity via the relief of a voltage-dependent Mg 2+ block. 3 The neuronal death induced by 3-NP displayed both apoptotic and necrotic features, 4 but exact molecular mechanisms underlying mixed forms of cell death are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum

Zhang

Wang²,

Wang³

et al. 2009

Autophagy

106

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“…The other pathological features observed in HD include loss of mitochondria and other supporting cytoplasmic organelles which are involved in the biosynthesis, modification, transport and degradation of cellular molecules [4]. HD has an estimated global prevalence of 4-5 per 100,000 in all the ethnic groups [5].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington’s disease

2015

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3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces neuropathological changes similar to those observed in Huntington's disease (HD). The objective of the present study was to investigate neuroprotective effect of mitochondrial modulators; alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) on 3-NP-induced alterations in mitochondrial lipid composition, mitochondrial structure and memory functions. Experimental model of HD was developed by administering 3-NP at sub-chronic doses, twice daily for 17 days. The levels of conjugated dienes, cholesterol and glycolipids were significantly increased, whereas the levels of phospholipids (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine) including cardiolipin were significantly decreased in the mitochondria isolated from the striatum of 3-NP-treated animals. In addition, the difference in molecular composition of each phospholipid class was also evaluated using mass spectrometry. Mitochondria lipid from 3-NP-treated animals showed increased cholesterol to phospholipid ratio, suggesting decreased mitochondrial membrane fluidity. 3-NP administration also resulted in ultra-structural changes in mitochondria, accompanied by swelling as assessed by transmission electron microscopy. The 3-NP administered animals had impaired spatial memory evaluated using elevated plus maze test. However, combined supplementation with ALA + ALCAR for 21 days normalized mitochondrial lipid composition, improved mitochondrial structure and ameliorated memory impairments in 3-NP-treated animals, suggesting an imperative role of these two modulators in combination in the management of HD.

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3-Nitropropionic acid induces cell death and mitochondrial dysfunction in rat corticostriatal slice cultures

Cited by 18 publications

References 21 publications

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum

Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington’s disease

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