l-BOAA induces selective inhibition of brain mitochondrial enzyme, NADH-dehydrogenase

Pai, Karnire S.; Ravindranath, Vijayalakshmi

doi:10.1016/0006-8993(93)90109-z

Cited by 28 publications

(9 citation statements)

References 37 publications

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“…32,33,20 The present study indicates that [ 3 H]glutamic acid binding was not only significantly inhibited in rats fed with 50% low and high toxin lathyrus but also in guinea pigs exposed to 10, 50 and 80% lathyrus, emphasizing the role of non-NMDA receptors in lathyrism. The mechanism of action of lathyrus may mimic excitatory amino acid because β-L-ODAP is chemically and pharmacologically similar to glutamic acid.…”

Section: Discussionmentioning

confidence: 72%

Comparative effect of dietary administration of Lathyrus sativus pulse on behaviour, neurotransmitter receptors and membrane permeability in rats and guinea pigs

Amba

Seth

Ali

et al. 2002

J of Applied Toxicology

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Neurolathyrism, an upper motor neuron disease, has been thought to be caused by long-term dietary consumption of lathyrus pulse, which contains the toxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid. Earlier behavioural studies employing oral feeding of lathyrus pulse to animals has been conducted without evaluating the biochemical toxicity potential. In the present investigation the effect of dietary feeding of 10%, 50% and 80% lathyrus pulse to rats and guinea pigs for 3 months on neurobehavioural parameters, including locomotor activity, inclined plain test and neurotoxicological parameters such as neurotransmitter receptor binding, Ca(2+) influx and membrane fluidity, was investigated. Exposure of 50% low and high toxin lathyrus to rats did not cause any significant change in locomotor activity, whereas guinea pigs at the same dosage regimen of high toxin lathyrus showed significant lowering of inclined plain test scores. Furthermore, studies of neuroreceptor binding in rats fed 50% low and high toxin lathyrus showed significant changes in glutamate, dopamine and muscarinic receptors, whereas the benzodiazepine receptor elicited no change. Guinea pigs, on the other hand, fed 50% and 80% lathyrus in the diet showed significant changes in glutamate, dopamine, muscarinic and benzodiazepine receptors. Interestingly, significant elevation in intracellular calcium with a concomitant increase in membrane fluidity was observed in rats (50% low and high toxin) and guinea pigs (50% and 80%) fed a lathyrus diet. These results indicate that although both species (rats and guinea pigs) are susceptible to neurochemical changes on exposure to lathyrus, locomotor changes are only noticed in guinea pigs. Thus, guinea pigs may be more prone to lathyrus toxicity and may serve as a sensitive animal model compared with rats.

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Section: Discussionmentioning

confidence: 72%

Comparative effect of dietary administration of Lathyrus sativus pulse on behaviour, neurotransmitter receptors and membrane permeability in rats and guinea pigs

Amba

Seth

Ali

et al. 2002

J of Applied Toxicology

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“…This in our view is perhaps due to an overemphasis of the structural similarities between ODAP and the dicarboxyhic amino acids, particularly that of glutamate, with the result that most investigators have examined in particular only enzymes related to the metabolism of acidic amino acids without any positive findings. Even the inhibition of NADH dehydrogenase by ODAP observed in a recent study with mouse brain slices (Pai and Ravindranath, 1993) has been shown to be a nonselective event by Sabri et al (1995).…”

Section: Discussionmentioning

confidence: 83%

“…Although L-ODAP has not been shown to affect directly the activity of any enzyme examined so far, the activity of certain enzymes such as brain lysosomal acid hydrolases (Lakshmanan et al, 1971), glutamate dehydrogenase (Duque-Magalhaes and Packer, 1972), and NADH dehydrogenase (Pai and Ravindranath, 1993;Sabri et al, 1995) has been found to be altered following L-ODAP treatment. It is interesting that despite its structural similarity to the dicarboxylic amino acids, L-ODAP has no effect on any of the enzymes of glutamate and aspartate metabolism (Jacob et al, 1967).…”

mentioning

confidence: 97%

Inhibition of Tyrosine Aminotransferase by β‐N‐Oxalyl‐l‐α,β‐Diaminopropionic Acid, the Lathyrus sativus Neurotoxin

Vardhan

Rudra

Rao

1997

Journal of Neurochemistry

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Species differences in susceptibility are a unique feature associated with the neurotoxicity of β‐N‐oxalyl‐l‐α,β‐diaminopropionic acid (l‐ODAP), the Lathyrus sativus neurotoxin, and the excitotoxic mechanism proposed for its mechanism of toxicity does not account for this feature. The present study examines whether neurotoxicity of l‐ODAP is the result of an interference in the metabolism of any amino acid and if it could form the basis to explain the species differences in susceptibility. Thus, Wistar rats and BALB/c (white) mice, which are normally resistant to l‐ODAP, became susceptible to it following pretreatment with tyrosine (or phenylalanine), exhibiting typical neurotoxic symptoms. C57BL/6J (black) mice were, however, normally susceptible to l‐ODAP without any pretreatment with tyrosine. Among the various enzymes associated with tyrosine metabolism examined, the activity of only tyrosine aminotransferase (TAT) was inhibited specifically by l‐ODAP. The inhibition was noncompetitive with respect to tyrosine (Ki = 2.0 ± 0.1 mM) and uncompetitive with respect to α‐ketoglutarate (Ki = 8.4 ± 1.5 mM). The inhibition of TAT was also reflected in a marked decrease in the rate of oxidation of tyrosine by liver slices, an increase in tyrosine levels of liver, and also a twofold increase in the dopa and dopamine contents of brain in l‐ODAP‐injected black mice. The dopa and dopamine contents in the brain of only l‐ODAP‐injected white mice did not show any change, whereas levels of these compounds were much higher in tyrosine‐pretreated animals. Also, the radioactivity associated with tyrosine, dopa, and dopamine arising from [14C]tyrosine was twofold higher in both liver and brain of l‐ODAP‐treated black mice. Thus, a transient increase in tyrosine levels following the inhibition of hepatic TAT by l‐ODAP and its increased availability for the enhanced synthesis of dopa and dopamine and other likely metabolites (toxic?) resulting therefrom could be the mechanism of neurotoxicity and may even underlie the species differences in susceptibility to this neurotoxin.

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“…Further demonstration of the difference in toxic potency between L-BOAA and L-BMAA was obtained in an in vitro model consisting of sagittal slices of mouse brain (Pai et al, 1993a(Pai et al, , 1993b. Incubation of such slices with BOAA (1 pM) resulted in significant leakage of lactate dehydrogenase (LDH) and potassium from the slices into the medium.…”

Section: In Vitro Studiesmentioning

confidence: 99%

Analysis, occurrence, and toxicity of ß-methylaminoalanine (BMAA)

2007

TemaNord

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l-BOAA induces selective inhibition of brain mitochondrial enzyme, NADH-dehydrogenase

Cited by 28 publications

References 37 publications

Comparative effect of dietary administration of Lathyrus sativus pulse on behaviour, neurotransmitter receptors and membrane permeability in rats and guinea pigs

Comparative effect of dietary administration of Lathyrus sativus pulse on behaviour, neurotransmitter receptors and membrane permeability in rats and guinea pigs

Inhibition of Tyrosine Aminotransferase by β‐N‐Oxalyl‐l‐α,β‐Diaminopropionic Acid, the Lathyrus sativus Neurotoxin

Analysis, occurrence, and toxicity of ß-methylaminoalanine (BMAA)

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