Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid in rats: implications for neuroprotection studies

Ouary, Stéphane; Bizat, Nicolas; Altairac, Séverine; Ménétrat, H; Mittoux, Vincent; Condé, Françoise; Hantraye, Philippe; Brouillet, Emmanuel

doi:10.1016/s0306-4522(00)00020-8

Cited by 104 publications

(121 citation statements)

References 28 publications

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“…However, all 3NP-treated rats showed symptoms of drowsiness, slowness of movement, and general uncoordination at D3. After 5 days, all animals were lying in a recumbent position and showed typical paddling movements of hind limbs, in agreement with previous description of this intoxication model (Bizat et al, 2003a;Garcia et al, 2002;Mittoux et al, 2002;Ouary et al, 2000).…”

Section: Rodent Model Of Huntington's Diseasesupporting

confidence: 90%

pH as a Biomarker of Neurodegeneration in Huntington's Disease: A Translational Rodent-Human MRS Study

Chaumeil

Valette

Baligand

et al. 2012

J Cereb Blood Flow Metab

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Early diagnosis and follow-up of neurodegenerative diseases are often hampered by the lack of reliable biomarkers. Neuroimaging techniques like magnetic resonance spectroscopy (MRS) offer promising tools to detect biochemical alterations at early stages of degeneration. Intracellular pH, which can be measured noninvasively by 31 P-MRS, has shown variations in several brain diseases. Our purpose has been to evaluate the potential of MRS-measured pH as a relevant biomarker of early degeneration in Huntington's disease (HD). We used a translational approach starting with a preclinical validation of our hypothesis before adapting the method to HD patients. 31 P-MRS-derived cerebral pH was first measured in rodents during chronic intoxication with 3-nitropropionic acid (3NP). A significant pH increase was observed early into the intoxication protocol (pH = 7.17±0.02 after 3 days) as compared with preintoxication (pH = 7.08 ± 0.03). Furthermore, pH changes correlated with the 3NP-induced inhibition of succinate dehydrogenase and preceded striatum lesions. Using a similar MRS approach implemented on a clinical MRI, we then showed that cerebral pH was significantly higher in HD patients (n = 7) than in healthy controls (n = 6) (7.05±0.03 versus 7.02 ± 0.01, respectively, P = 0.026). Altogether, both preclinical and human data strongly argue in favor of MRS-measured pH being a promising biomarker for diagnosis and follow-up of HD.

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Section: Rodent Model Of Huntington's Diseasesupporting

confidence: 90%

pH as a Biomarker of Neurodegeneration in Huntington's Disease: A Translational Rodent-Human MRS Study

Chaumeil

Valette

Baligand

et al. 2012

J Cereb Blood Flow Metab

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Section: Discussionmentioning

confidence: 99%

“…The susceptibility to the neurotoxic effects of 3-NP administration is strain dependent [19,20] . In rat and mouse strains, Lewis rat and C57BL/6 mouse were reported to respond poorly to 3-NP toxicity [19,20] . The impaired cognitive performance following 3-NP treatment could be detected in Wistar and Sprague-Dawley rats [9,21,22] , but not seen in Lewis rats [17,22] .…”

Section: Discussionmentioning

confidence: 99%

No spatial memory deficit exists in Kunming mice that recently recovered from motor defects following 3-nitropropionic acid intoxication

Zhu

et al. 2009

Neurosci. Bull.

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Objective Numerous studies have described both motor defects and cognitive impairments in several strains of rodents following 3-nitropropionic acid (3-NP) intoxication. In the present study, we investigated spatial recognition memory in Kunming mice that just recovered from motor defects induced by 3-NP. Methods Mouse model was made by systemic subacute 3-NP treatment, and spatial recognition memory was measured through the Y-maze Test, a simple two-trial recognition test. Results (1) On day 15 following 3-NP treatment, affected Kunming mice did not show motor defects in the Rotarod test and presented normal gait again. (2) In the following Y-maze test after 1h interval, the percentage (90.0%) of mice showing novel arm preference in 3-NP treatment group was significantly higher than the random chance level (50%), although it was only slightly higher than that (83.3%) in control group. On day 45 after 3-NP treatment, mice failed to choose unfamiliar novel arm as first choice, and the same occured in the control group. (3) For both post-intoxicated (on day 15 and day 45 following 3-NP treatment) and control groups, the duration in the novel arm and the frequency of entering it, were longer and higher compared with familiar start and other arms. For these mice that recently recovered from motor defects following 3-NP intoxication, no spatial memory deficits were observed through Y-maze Test. Conclusion Kunming mice used in our assays might possess resistance to cognitive impairment induced by 3-NP, which is consistent with previous findings in Swiss EPM-M1 mice.

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“…3-Nitropropionic acid is an irreversible inhibitor of mitochondrial complex II that causes dystonia in humans as well as rodents. 67,91,92 The obvious parallels with dystonia in humans are a clear advantage, so this model merits further scrutiny. Systemically administered Bay K 8644, an Ltype calcium channel agonist, causes generalized dystonia in both rats and mice.…”

Section: Empirical Discoverymentioning

confidence: 99%

Experimental Therapeutics for Dystonia

Jinnah

Hess

2008

Neurotherapeutics

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Summary: Dystonia is a neurological syndrome characterized by excessive involuntary muscle contractions leading to twisting movements and unnatural postures. It has many different clinical manifestations, and many different causes. More than 3 million people worldwide suffer from dystonia, yet there are few broadly effective treatments. In the past decade, progress in research has advanced our understanding of the pathogenesis of dystonia to a point where drug discovery efforts are now feasible. Several strategies can be used to develop novel therapeutics for dystonia. Existing therapies have only modest efficacy, but may be refined and improved to increase benefits while reducing side effects. Identifying rational targets for drug intervention based on the pathogenesis of dystonia is another strategy. The surge in both basic and clinical research discoveries has provided insights at all levels, including etiological, physiological and nosological, to enable such a targeted approach. The empirical approach to drug discovery, whereby compounds are identified using a nonmechanistic strategy, is complementary to the rational approach. With the recent development of multiple animal models of dystonia, it is now possible to develop assays and perform drug screens on vast numbers of compounds. This multifaceted approach to drug discovery in dystonia will likely provide lead compounds that can then be translated for clinical use.

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Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid in rats: implications for neuroprotection studies

Cited by 104 publications

References 28 publications

pH as a Biomarker of Neurodegeneration in Huntington's Disease: A Translational Rodent-Human MRS Study

pH as a Biomarker of Neurodegeneration in Huntington's Disease: A Translational Rodent-Human MRS Study

No spatial memory deficit exists in Kunming mice that recently recovered from motor defects following 3-nitropropionic acid intoxication

Experimental Therapeutics for Dystonia

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