L-2-Chloropropionic Acid-Induced Neurotoxicity Is Prevented by MK-801: Possible Role of NMDA Receptors in the Neuropathology

Widdowson, PS; Wyatt, I. J.; Gyte, Andrew; Simpson, MG; Lock, Edward A.

doi:10.1006/taap.1996.0017

Cited by 15 publications

(6 citation statements)

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“…Studies suggest that 2‐CPA‐induced cerebellar granule cell necrosis may occur via an excitotoxic mechanism, involving the NMDA receptor. Administration of the non‐competitive NMDA antagonist, MK‐801, to rats 30 min before, or 1 h after 2‐CPA, prevented the cerebellar toxicity (Widdowson et al . 1996a; Lock et al .…”

Section: ‐Halopropionic Acidsmentioning

confidence: 99%

The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells

Fonnum

Lock

2003

Journal of Neurochemistry

110

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Six chemicals, 2-halopropionic acids, thiophene, methylhalides, methylmercury, methylazoxymethanol (MAM) and trichlorfon ( Fig. 1), that cause selective necrosis to the cerebellum, in particular to cerebellar granule cells, have been reviewed. The basis for the selective toxicity to these neurones is not fully understood, but mechanisms known to contribute to the neuronal cell death are discussed. All six compounds decrease cerebral glutathione (GSH), due to conjugation with the xenobiotic, thereby reducing cellular antioxidant status and making the cells more vulnerable to reactive oxygen species. 2-Halopropionic acids and methylmercury appear to also act via an excitotoxic mechanism leading to elevated intracellular Ca 2+ , increased reactive oxygen species and ultimately impaired mitochondrial function. In contrast, the methylhalides, trichlorfon and MAM all methylate DNA and inhibit O 6 -guanine-DNA methyltransferase (OGMT), an important DNA repair enzyme. We propose that a combination of reduced antioxidant status plus excitotoxicity or DNA damage is required to cause cerebellar neuronal cell death with these chemicals. The small size of cerebellar granule cells, the unique subunit composition of their N-methyl-D-aspartate (NMDA) receptors, their low DNA repair ability, low levels of calcium-binding proteins and vulnerability during postnatal brain development and distribution of glutathione and its conjugating and metabolizing enzymes are all important factors in determining the sensitivity of cerebellar granule cells to toxic compounds.

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Section: ‐Halopropionic Acidsmentioning

confidence: 99%

The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells

Fonnum

Lock

2003

Journal of Neurochemistry

110

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“…Prior administration of MK‐801 (5 mg/kg i.p.) to l ‐CPA‐treated animals (single oral dose; 750 mg/kg) has been reported to result in protection in that rats exhibited normal locomotor function and cerebellar morphology 96 h after l ‐CPA administration (Widdowson et al . 1996b).…”

mentioning

confidence: 99%

“…The involvement of NMDA receptors in the selective neurotoxicity induced by l ‐CPA has been demonstrated (Widdowson et al . 1996b); however, the exact mechanism for NMDA receptor‐mediated neuronal death is not clear.…”

mentioning

confidence: 99%

“…1996b); however, the exact mechanism for NMDA receptor‐mediated neuronal death is not clear. It has been suggested that l ‐CPA may mimic glutamate at the glutamate binding site of cerebellar NMDA receptors (Widdowson et al . 1996b) or that selective neurotoxicity of l ‐CPA may be potentiated by a difference in glycine modulation at cerebellar NMDA receptors.…”

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confidence: 99%

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Neuroprotective effects of MK‐801 on l‐2‐chloropropionic acid‐induced neurotoxicity

Williams

Lock

Bachelard

2001

Journal of Neurochemistry

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L-2-Chloropropionic acid is selectively toxic to the cerebellum in rats; the granule cell necrosis observed within 48 h can be prevented by prior administration of MK-801. Short-term treatment (2 h) with L-2-chloropropionic acid has also been shown to activate the mitochondrial pyruvate dehydrogenase complex in fasted adult rats. This study aimed to investigate the effect of prior exposure to MK-801 on the biochemical and neurotoxicological effects of L-2-chloropropionic acid. Extracts were prepared from the forebrain and cerebellum of animals that had been treated with L-2-chloropropionic acid, with and without prior treatment with MK-801, and were analysed using magnetic resonance spectroscopy and amino acid analysis. Glucose metabolism was studied by monitoring the metabolism of [1-13 C]-glucose using GC/MS. L-2-Chloropropionic acid caused increased glucose metabolism in both brain regions 6 h after administration, con®rming activation of the pyruvate dehydrogenase complex, which was not prevented by MK-801. After 48 h an increase in lactate and a decrease in N-acetylaspartate was observed only in the cerebellum, whereas phosphocreatine and ATP decreased in both tissues. MK-801 prevented the changes in lactate and N-acetylaspartate, but not those on the energy state. These studies suggest that L-2-chloropropionic acid-induced neurotoxicity is only partly mediated by the NMDA subtype of glutamate receptor.

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“…The involvement of excitatory amino acids in the L-CPA neurotoxicity has been demonstrated with the prevention of the granule cell necrosis and resultant oedema by co-administration of N-methyl-D-aspartate receptor antagonist, MK-801 (Widdowson et al, 1996b). We have further explored L-CPA neurotoxicity by examining the role of nitric oxide which may lead to neuronal cell death as glutamate excitotoxicity has been shown to be mediated by nitric oxide production in primary cortical cultures (Dawson et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Evidence for mediation of L‐2‐chloropropionic acid‐induced delayed neuronal cell death by activation of a constitutive nitric oxide synthase

Widdowson

Farnworth

Moore

et al. 1996

British J Pharmacology

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1 Delayed neuronal cell death elicited by excess excitatory amino acid concentrations has been strongly implicated in many neurological disorders including head trauma, stroke, motor neurone disease and Huntington's disease. We have used the neurotoxin, L-2-chloropropionic acid (L-CPA) to 3 Quantitative autoradiography using [3H]-N0-nitro-L-arginine was used to measure the relative anatomical distribution and amount of NOS enzyme in the cerebellum of controls and L-CPA-treated rats 48 h following dosing. There was no significant alteration in the binding of [3H]-N0-nitro-L-arginine to granular and molecular layers of the cerebellum of control and L-CPA-treated rat brains. 4 Western blotting using antibodies against the inducible NOS enzyme failed to detect the protein in cerebellums of L-CPA-treated rats when measured 48 h after L-CPA dosing. 5 In conclusion, the increase in cerebellar nitrate/nitrite concentrations in L-CPA-treated rats provides further evidence for activation of NOS in the cerebellum following administration of L-CPA. The failure to demonstrate an increase in NOS activity at 6 or 48 h in L-CPA-treated rats as compared to controls suggests that the source of nitric oxide responsible for the granule cell death must originate from the constitutive NOS enzyme, probably the neuronal form which is highly enriched in the cerebellum. This hypothesis was further substantiated by Western blotting and quantitative autoradiography.

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L-2-Chloropropionic Acid-Induced Neurotoxicity Is Prevented by MK-801: Possible Role of NMDA Receptors in the Neuropathology

Cited by 15 publications

References 0 publications

The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells

The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells

Neuroprotective effects of MK‐801 on l‐2‐chloropropionic acid‐induced neurotoxicity

Evidence for mediation of L‐2‐chloropropionic acid‐induced delayed neuronal cell death by activation of a constitutive nitric oxide synthase

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