Protective Effect of l‐Carnitine in the Neurotoxicity Induced by the Mitochondrial Inhibitor 3‐Nitropropionic Acid (3‐NPA)

Binienda, Zbigniew; Johnson, John R.; Tyler-Hashemi, Alexander A.; Rountree, Robert; Sapienza, P.P.; Ali, Syed F.; Kim, Chung S.

doi:10.1111/j.1749-6632.1999.tb07992.x

Cited by 21 publications

(18 citation statements)

References 11 publications

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“…3NPA induces neurodegeneration in the caudate putamen in humans and experimental animals, resembling Huntington's disease. [3][4][5][6][7][8] Consequently, 3NPA poisoning is used primarily as an animal model of selective neurodegeneration. The mechanism of toxicity is thought to be because of the irreversible, covalent binding of 3NPA with subsequent inhibition of succinate dehydrogenase (SDH), an enzyme of the citric acid cycle that transfers electrons to the electron transport chain via its complex II function.…”

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confidence: 99%

Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice

Gabrielson

Hogue

Bohr

et al. 2001

The American Journal of Pathology

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We investigated the effects of 3-nitropropionic acid (3NPA), a previously characterized neurotoxin, in four strains of mice to better understand the molecular basis of variable host responses to this agent. Unexpectedly, we found significant cardiac toxicity that always accompanied the neurotoxicity in all strains of mice in acute and subacute/chronic toxicity testing. Caudate putamen infarction never occurred without cardiac toxicity. All mouse strains tested are sensitive to 3NPA although the C57BL/6 and BALB/c mice require more exposure than 129SVEMS and FVB/n mice. Cardiac toxicity alone was found in 50% of symptomatic mice tested and morphologically, the cardiac toxicity is characterized by diffuse swelling of cardiomyocytes and multifocal coagulative contraction band necrosis. In subacute to chronic exposure, atrial thrombosis, cardiac mineralization, cell loss, and fibrosis are combined with cardiomyocyte swelling and necrosis. Ultrastructurally, mitochondrial swelling occurs initially, followed by disruption of myofilaments. Biochemically, isolated heart mitochondria from the highly sensitive 129SVEMS mice have a significant reduction of succinate dehydrogenase activity, succinate oxygen consumption rates, and heart adenosine triphosphate after 3NPA treatment. The severity of morphological changes parallels the biochemical alterations caused by 3NPA, consistent with cardiac toxicity being a consequence of the effects of 3NPA on succinate dehydrogenase. These experiments show, for the first time, that 3NPA has important cardiotoxic effects as well as neurotoxic effects, and that cardiac toxicity possibly resulting from inhibition of the succinate dehydrogenase in heart mitochondria, contributes to the cause of death in 3NPA poisoning in acute and subacute/chronic studies in mice.

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confidence: 99%

Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice

Gabrielson

Hogue

Bohr

et al. 2001

The American Journal of Pathology

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“…LC attenuated 3‐NPA‐induced rat cortical cell damage in vitro 20. In our animal model, pretreatment with LC prevented the increase in endogenous free radical scavenging enzymes, including catalase and superoxide dismutase, observed when 3‐NPA was administered alone 21…”

Section: Animal Model Of Mitochondrial Dysfunctionmentioning

confidence: 64%

l‐Carnitine and Neuroprotection in the Animal Model of Mitochondrial Dysfunction

Binienda

Przybyla-Zawislak

Virmani

et al. 2005

Annals of the New York Academy of Sciences

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We have shown previously that pretreatment with l‐carnitine (LC) prior to 3‐nitropropionic acid (3‐NPA) exposure, while not significantly attenuating succinate dehydrogenase (SDH) inhibition, prevented hypothermia and oxidative stress. The plant and fungal toxin, 3‐NPA, acts as an inhibitor of mitochondrial function via irreversible inactivation of the mitochondrial inner membrane enzyme, SDH. Inhibition of SDH disturbs electron transport, leading to cellular energy deficits and oxidative stress‐related neuronal injury. In the study presented here, a neurohistological method was applied to examine the mitochondriotropic effect of LC pretreatment against 3‐NPA‐induced neurotoxicity. Twenty adult male Sprague‐Dawley rats randomly divided into two groups (n= 10/group) were injected twice with 3‐NPA at 30 mg/kg sc, at 2 days apart, or received LC pretreatment at 100 mg/kg, at 30‐40 min before 3‐NPA administration. Rats in both groups were perfused 7 days later and their brains harvested. Degenerating neurons were identified and localized via the fluorescent marker Fluoro‐Jade B. Data analysis showed that LC was protective against 3‐NPA‐induced toxicity, as reflected by both reduced mortality and significantly reduced neuronal degeneration.

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“…Investigations of coenzyme Q10, which has the ability to increase ATP production as well as acting as a potent antioxidant, particularly in lipophilic membranes, have shown a neuroprotective propensity against both MPTP, malonate and 3-nitropropionic acid induced toxicity (Beal et al, 1994). Other compounds, e.g., lamotrigine and MK-801 and L-carnitine (Binienda et al, 1999) possess neuroprotective efficacy against the toxicity of 3-nitropropionic acid. Other compounds, e.g., lamotrigine and MK-801 and L-carnitine (Binienda et al, 1999) possess neuroprotective efficacy against the toxicity of 3-nitropropionic acid.…”

Section: Agents Of Neuroprotectionmentioning

confidence: 99%

Neuroprotective and neurorestorative strategies for neuronal injury

et al. 2000

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Mechanisms of neuronal cell death in apoptosis and necrosis are examined. Neurotoxic processes underlying cellular destruction may involve N-methyl-D-aspartate (NMDA) receptor activation and/or activation of neuronal nitric oxide synthase but the depletion of energy and generation of free radicals appears to be critical. In Alzheimer's disease the damaging effects of peroxynitrite and exposure to beta-amyloid peptide is evident. Mitochondrial dysfunction is involved in several neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease as well as Alzheimer's disease and in these disorders the innovations offered by techniques ranging from transgenic mouse models of the disorder to cell culture preparations are remarkable. Agents of neuroprotection and neurorestoration possess either characteristics specific to particular disorders or have a general applicability or both. The vast array of agents available are for the most part the objectives of laboratory examinations but an increasing selection of compounds are reaching the clinical necessities thereby influencing current strategic notions to modify tactical contingencies. Among the agents listed are included: inhibitors of the enzyme poly-ADP-ribose polymerase, inhibition of apoptotic cell death, agents acting on mitochondrial permeability transition, excitatory amino acid antagonists, applications of neurotrophins, immunophilins, agents influencing heme oxygenase-1 expression and iron sequestration in aging astroglia, improvements in mitochondrial energy production or buffering, and finally dopaminemimetics with differential affinities for dopamine receptors.

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Protective Effect of l‐Carnitine in the Neurotoxicity Induced by the Mitochondrial Inhibitor 3‐Nitropropionic Acid (3‐NPA)

Cited by 21 publications

References 11 publications

Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice

Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice

l‐Carnitine and Neuroprotection in the Animal Model of Mitochondrial Dysfunction

Neuroprotective and neurorestorative strategies for neuronal injury

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