Partial Inhibition of Brain Succinate Dehydrogenase by 3‐Nitropropionic Acid Is Sufficient to Initiate Striatal Degeneration in Rat

Brouillet, Emmanuel; Guyot, Marie-Caroline; Mittoux, Vincent; Altairac, Séverine; Condé, Françoise; Palfi, Stéphane; Hantraye, Philippe

doi:10.1046/j.1471-4159.1998.70020794.x

Cited by 198 publications

(152 citation statements)

References 31 publications

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“…The present FDG studies demonstrate that the sensitivity and temporal (Ϸ1 s) and spatial resolution (0.8 mm with 18 F-radiolabeled tracers) of the ␤-MICROPROBE system permits the quantitative assessment of even modest changes in regional metabolic activity in individual rats.…”

Section: Anaesthetized Ratsmentioning

confidence: 70%

“…Semiquantitative measurement of succinate dehydrogenase inhibition was performed as described (18). The images of each section were acquired with CYTOSTAR (IMSTAR) and quantified as reported (18).…”

Section: Methodsmentioning

confidence: 99%

“…The images of each section were acquired with CYTOSTAR (IMSTAR) and quantified as reported (18). Data Analysis.…”

Section: Methodsmentioning

confidence: 99%

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In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β ⁺ -sensitive microprobe

Pain¹,

Besret²,

Vaufrey³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Understanding brain disorders, the neural processes implicated in cognitive functions and their alterations in neurodegenerative pathologies, or testing new therapies for these diseases would benefit greatly from combined use of an increasing number of rodent models and neuroimaging methods specifically adapted to the rodent brain. Besides magnetic resonance (MR) imaging and functional MR, positron-emission tomography (PET) remains a unique methodology to study in vivo brain processes. However, current high spatialresolution tomographs suffer from several technical limitations such as high cost, low sensitivity, and the need of restraining the animal during image acquisition. We have developed a ␤ ؉ -sensitive high temporal-resolution system that overcomes these problems and allows the in vivo quantification of cerebral biochemical processes in rodents. This ␤-MICROPROBE is an in situ technique involving the insertion of a fine probe into brain tissue in a way very similar to that used for microdialysis and cell electrode recordings. In this respect, it provides information on molecular interactions and pathways, which is complementary to that produced by these technologies as well as other modalities such as MR or fluorescence imaging. This study describes two experiments that provide a proof of concept to substantiate the potential of this technique and demonstrate the feasibility of quantifying brain activation or metabolic depression in individual living rats with 2-[ 18 F]fluoro-2-deoxy-D-glucose and standard compartmental modeling techniques. Furthermore, it was possible to identify correctly the origin of variations in glucose consumption at the hexokinase level, which demonstrate the strength of the method and its adequacy for in vivo quantitative metabolic studies in small animals.A lterations in local cerebral metabolic rate of glucose (lCMRglc) have been reported in several human brain conditions such as psychiatric disorders or neurodegenerative diseases. Understanding the cellular mechanisms involved in these diseases and the development of new therapeutic strategies will advance more rapidly through the use of animal models. The quantitation of metabolic rates in the rodent brain was achieved initially by using the 2-deoxy-D-[ 14 C]glucose autoradiographic method (1). Although efficient, this technique requires the sacrifice of several animals to obtain each time point and thus can provide only ex vivo, averaged kinetic constants calculated from values obtained from various animals. As an alternative, positron-emission tomography (PET), an imaging technology designed to use compounds labeled with positron-emitting radioisotopes to image and measure biochemical processes in vivo, has been adapted to use in small animals. The implementation of several high spatial-resolution PET scanners within the last several years (2-9) has enabled the adaptation of the 2-deoxy-D-[ 14 C]glucose method to in vivo imaging of small animals by using 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) as a tracer. However, such PE...

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Section: Anaesthetized Ratsmentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

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In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β ⁺ -sensitive microprobe

Pain¹,

Besret²,

Vaufrey³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Several studies have reported the occurrence of mitochondrial dysfunction in brains from Huntington disease (HD) patients, namely, through the inhibition of respiratory chain complexes II and III (Browne et al, 1997;Gu et al, 1996). Systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, was shown to elicit behavioral abnormalities and cortical and striatal neuronal degeneration in rats and nonhuman primates, similar to that seen in humans with HD (Beal et al, 1993;Brouillet et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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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“…Indeed, chronic systemic administration of 3NP in rats and non-human primates produces homogenous blockade of complex II within the brain (17), leading to preferential excitotoxic striatal degeneration associated with behavioral abnormalities that are highly reminiscent of HD (18 -20).…”

mentioning

confidence: 99%

In Vivo Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration

Bizat¹,

Hermel²,

Humbert

et al. 2003

Journal of Biological Chemistry

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123

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The role of caspases and calpains in neurodegeneration remains unclear. In this study, we focused on these proteases in a rat model of Huntington's disease using the mitochondrial toxin 3-nitropropionic acid (3NP). Results showed that 3NP-induced death of striatal neurons was preceded by cytochrome c redistribution, transient caspase-9 processing, and activation of calpain, whereas levels of the active/processed form of caspase-3 remained low and were even reduced as compared with control animals. We evidenced here that this decrease in active caspase-3 levels could be attributed to calpain activation. Several observations supported this conclusion. 1) Pharmacological blockade of calpain in 3NP-treated rats increased the levels of endogenous processed caspase-9 and caspase-3. 2) Cell-free extracts prepared from the striatum of 3NP-treated rats degraded in vitro the p34 and p20 subunits of active recombinant caspase-9 and caspase-3, respectively. 3) This degradation of p34 and p20 could be mimicked by purified -calpain and was prevented by calpain inhibitors. 4) -Calpain produced a loss of the DEVDase (Asp-GluVal-Asp) activity of active caspase-3. 5) Western blot analysis and experiments with 35 S-radiolabeled caspase-3 showed that -calpain cleaved the p20 subunit of active caspase-3 near its catalytic site. 6) -Calpain activity was selectively inhibited (IC 50 of 100 M) by a 12 amino acid peptide corresponding to the C terminus of p20. Our results showed that calpain can down-regulate the caspase-9/caspase-3 cell death pathway during neurodegeneration due to chronic mitochondrial defects in vivo and that this effect may involve, at least in part, direct cleavage of the caspase-3 p20 subunit.

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Partial Inhibition of Brain Succinate Dehydrogenase by 3‐Nitropropionic Acid Is Sufficient to Initiate Striatal Degeneration in Rat

Cited by 198 publications

References 31 publications

In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β ⁺ -sensitive microprobe

In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β ⁺ -sensitive microprobe

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

In Vivo Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration

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Partial Inhibition of Brain Succinate Dehydrogenase by 3‐Nitropropionic Acid Is Sufficient to Initiate Striatal Degeneration in Rat

Cited by 198 publications

References 31 publications

In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β + -sensitive microprobe

In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β + -sensitive microprobe

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

In Vivo Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration

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In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β ⁺ -sensitive microprobe

In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β ⁺ -sensitive microprobe