Apoptosis in the striatum of rats following intraperitoneal injection of 3-nitropropionic acid

Sato, Shuzo; Gobbel, Glenn T.; Honkaniemi, Jari; Li, Yibing; Kondo, Takeo; Murakami, Kensuke; Sato, Minako; Copin, Jean Christophe; Chan, Pak H.

doi:10.1016/s0006-8993(96)01231-0

Cited by 49 publications

(24 citation statements)

References 16 publications

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“…Thus, interrupting mitochondrial function with repetitive doses of 3-NP produced cellular damage like that earlier reported 3, 31. Neuronal damage produced by intraperitoneal administration of 3-NP in low doses, has been described at the onset of the neurodegenerative process 4, is restricted to striatal calbinding positive cells (unpublished data from our lab), may initiate necrotic death by excitotoxicity 19, and triggers apoptotic pathways in mice like it does in rats 32.…”

Section: Discussionsupporting

confidence: 66%

Uncoupling oxidative/energy metabolism with low sub chronic doses of 3-nitropropionic acid or iodoacetate in vivo produces striatal cell damage

Rodríguez

Rivera²,

Astorga³

et al. 2010

Int. J. Biol. Sci.

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A variety of evidence suggests that the failure of cellular metabolism is one of the underlying causes of neurodegenerative diseases. For example, the inhibition of mitochondrial function produces a pattern of cellular pathology in the striatum that resembles that seen in Huntington's disease. However, neurons can also generate ATP through the glycolytic pathway. Recent work has suggested a direct interaction between mutated huntingtin and a key enzyme in the glycolytic pathway, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Yet little work has been gone into examination of the cellular pathology that results from the inhibition of this alternative energy source. Therefore, the aim of the present study is to characterize the cellular pathology that results in the striatum of mice after treatment with a toxin (iodoacete, IOA) that compromises anaerobic metabolism. This striatal pathology is compared to that produced by a widely studied blocker of mitochondrial function (3-nitropropionic acid, 3-NP).We found that low doses of either toxin resulted in significant pathology in the mouse striatum. Signs of apoptosis were observed in both experimental groups, although apoptosis triggered by IOA treatment was independent from caspase-3 activation. Importantly, each toxin appears to produce cellular damage through distinct mechanisms; only 3-NP generated clear evidence of oxidative stress as well as inhibition of endogenous antioxidants. Understanding the distinct pathological fingerprints of cell loss produced by blockade of oxidative and anaerobic metabolisms may give us insights into neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 66%

Uncoupling oxidative/energy metabolism with low sub chronic doses of 3-nitropropionic acid or iodoacetate in vivo produces striatal cell damage

Rodríguez

Rivera²,

Astorga³

et al. 2010

Int. J. Biol. Sci.

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“…Interestingly, although tBHQ did not reduce damage to the striatal stroke core during transient MCAO, it significantly attenuated striatal neurodegeneration during 3-nitropropionic acid toxicity (Shih et al, 2005). Because 3-nitropropionic acid produces gradual and partial metabolic inhibition (Beal et al, 1993;Sato et al, 1997;Brouillet et al, 1998;Kim et al, 2000), it is in some ways similar to the salvageable cortical stroke penumbra.…”

Section: Nrf2 Dependency Of Tbhq-mediated Neuroprotectionmentioning

confidence: 99%

A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral IschemiaIn Vivo

Shih¹,

Li²,

Murphy³

2005

J. Neurosci.

389

289

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The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Previously, activation of this pleiotropic response was neuroprotective in cell culture models that simulate components of stroke damage. However, the role of Nrf2 in limiting stroke damage in vivo remained unclear. We report that Nrf2 activation protects the brain from cerebral ischemia in vivo. Acute (1-3 d) intracerebroventricular or intraperitoneal pretreatment with tert-butylhydroquinone (tBHQ), an Nrf2 activity inducer, reduced cortical damage and sensorimotor deficit at 24 h and even 1 month after ischemia-reperfusion in rats. Cortical glutathione levels robustly increased with tBHQ administration to rats and Nrf2-expressing mice, but not Nrf2 Ϫ/Ϫ mice. Basal and inducible activities of antioxidant/detoxification enzymes in Nrf2Ϫ/Ϫ mice were reduced when compared with Nrf2 ϩ/ϩ controls. Interestingly, larger infarcts were observed in Nrf2 Ϫ/Ϫ mice at 7 d after stroke, but not at 24 h, suggesting that Nrf2 may play a role in shaping the penumbra well after the onset of ischemia. Neuronal death caused by a "penumbral" model of stroke, using intracortical endothelin-1 microinjection, was attenuated by tBHQ administration to Nrf2 ϩ/ϩ , but not to Nrf2 Ϫ/Ϫ mice, confirming the Nrf2-specific action of tBHQ in vivo. We conclude that Nrf2 plays a role in modulating ischemic injury in vivo. Accordingly, Nrf2 activation by small molecule inducers may be a practical preventative treatment for stroke-prone patients.

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“…Systemic administration of 3-NP produces selective striatal legion damage and clinical features of Huntington's disease [8][9][10]. The effect of this agent in the cochlea can be regarded as insufficiency of cellular energy in the cochlea.…”

Section: Introductionmentioning

confidence: 99%

A novel animal model of acute cochlear mitochondrial dysfunction

et al. 2004

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Acute mitochondrial dysfunction in the cochlea is likely to result in hearing loss as a consequence of local energy shortage, similar to ischemia- or noise-induced hearing loss. To establish an animal model of acute cochlear mitochondrial dysfunction, we applied a mitochondrial toxin, 3-nitropropionic acid (3-NP) in the rat cochlea. Rats treated with 500mM 3-NP exhibited permanent threshold shifts in acoustic brainstem response while the same volume of 300mM 3-NP caused temporary threshold shifts. Histological examination in the permanent threshold shift model revealed severe degeneration of fibrocytes within spiral ligament and spiral limbus, indicating these cells are vulnerable to acute mitochondrial dysfunction. This model represents a novel tool for investigating the pathophysiology of acute cochlear mitochondrial dysfunction.

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Apoptosis in the striatum of rats following intraperitoneal injection of 3-nitropropionic acid

Cited by 49 publications

References 16 publications

Uncoupling oxidative/energy metabolism with low sub chronic doses of 3-nitropropionic acid or iodoacetate in vivo produces striatal cell damage

Uncoupling oxidative/energy metabolism with low sub chronic doses of 3-nitropropionic acid or iodoacetate in vivo produces striatal cell damage

A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral IschemiaIn Vivo

A novel animal model of acute cochlear mitochondrial dysfunction

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