L-2-chloropropionic acid-induced neurotoxicity in the rat: a valuable model for studying selective neuronal cell death in vivo.
1. L-2-Chloropropionic acid (L-CPA) is neurotoxic when administered orally as a neutral sodium salt in high doses to rats, resulting in a selective destruction of cerebellar granule cells with the result that animals develop marked difficulties in maintaining normal locomotion. 2. Cerebellar granule cell destruction is accompanied by a reduction in cerebellar glutamate and aspartate concentrations, reductions in the density of glutamate receptors located in the cerebellar granule cell layer and development of cerebellar oedema. No other cell type in the brain, nor other organ, is affected by L-CPA. 3. The neuronal cell death is necrotic in type, involving the activation of N-methyl-D-aspartate (NMDA) type glutamate receptors and there is some evidence for a partial role of nitric oxide in the development of the neurotoxicity. 4. Contrary to work performed on NMDA mediated cell death using neuronal cell culture approaches, L-CPA-induced granule cell death does not appear to arise from the production of excess quantities of cytotoxic free radicals, but may involve selective calcium-activated proteases, such as the calpains. 5. Tentative evidence suggests that L-CPA may interfere with voltage-dependent calcium channels in the cerebellum leading to activation of the cell death and resulting in the destruction of the granule cells. 6. In conclusion, L-CPA-induced neurotoxicity may provide valuable information on the neurochemical pathways involved in neuronal cell death that is associated with many neurological diseases.
Widdowson
P S
PS
Neurotoxicology Research Group, ZENECA Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Simpson
M G
MG
Wyatt
I
I
D000284:Administration, Oral; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D002154:Calpain / Q000378:metabolism; D002250:Carbon Radioisotopes; D016923:Cell Death / Q000187:drug effects*; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005609:Free Radicals; D006843:Hydrocarbons, Chlorinated; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats
D015220:Calcium Channels; D002250:Carbon Radioisotopes; D005609:Free Radicals; D006843:Hydrocarbons, Chlorinated; D011422:Propionates; C021974:2-chloropropionic acid; D019001:Nitric Oxide Synthase; D002154:Calpain