L-2-chloropropionic acid-induced neurotoxicity is prevented by MK-801: possible role of NMDA receptors in the neuropathology.
We have demonstrated that following a single oral dose of L-2-chloropropionic acid (L-CPA) to rats (750 mg/kg; pH 7) there was a marked and widespread loss of granule cells in the cerebellum as assessed by neuropathology by 48 hr. There also appeared to be limited damage to Purkinje cells, whereas stellate, Golgi, and basket cells were not affected by L-CPA administration. The L-CPA-mediated cerebellar neuropathology was accompanied by a significant increase in the cerebellar water content and sodium concentration, 48 hr following L-CPA administration, suggesting an edematous reaction. After 36 hr, the animals displayed marked locomotor dysfunction and had to be terminated at 54 hr due to marked weight loss. We did not observe any neuropathology in forebrain regions nor was the water content in the forebrain significantly different from controls in animals which had been treated with L-CPA. Cerebellar aspartate concentrations were reduced 48 hr following L-CPA administration becoming marked at 54 hr and accompanied by a significant reduction in cerebellar glutamate concentrations. The density of N-methyl-D-aspartate (NMDA) receptors in the granular layer of the cerebellar cortex was also significantly reduced at 48 and 54 hr following L-CPA administration. Prior administration of MK-801 (dizocilpine) (5 mg/kg/i.p.), an irreversible NMDA receptor antagonist, 30 min before an oral dose of L-CPA (750 mg/kg) prevented the loss of both granule and Purkinje cells. There was no abnormal locomotor activity in the L-CPA rats treated with MK-801 except for the first 4 hr following dosing when animals were severely sedated. Animals which received L-CPA plus MK-801 were normal 96 hr post dosing showing that MK-801 did not delay the onset of L-CPA toxicity. There was no alteration in cerebellar water content or sodium concentrations in rats which had been administered MK-801 with L-CPA. The reductions in cerebellar aspartate and glutamate concentrations were totally prevented by administration of MK-801, as was the reduction in L(-)[3H]glutamate binding to cerebellar NMDA receptors. Administration of MK-801 alone (5 mg/kg/i.p.) did not alter the water content, sodium concentrations, aspartate or glutamate concentrations, or the density of NMDA receptors in the cerebellum. In conclusion, we suggest that L-CPA-induced neurotoxicity leading to loss in granule cells and an accompanying cerebellar edema can be prevented by MK-801, suggesting that a subpopulation of NMDA receptors found on cerebellar granule cells play a pivotal role in mediating the toxicity of this compound.
Widdowson
P S
PS
Neurotoxicology Group, ZENECA Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom.
Wyatt
I
I
Gyte
A
A
Simpson
M G
MG
Lock
E A
EA
D000284:Administration, Oral; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001345:Autoradiography; D001929:Brain Edema / Q000139:chemically induced / Q000517:prevention & control; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000473:pathology; D006843:Hydrocarbons, Chlorinated; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D011422:Propionates / Q000008:administration & dosage / Q000633:toxicity*; D011690:Purkinje Fibers / Q000187:drug effects / Q000473:pathology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects; D013654:Taurine / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D006843:Hydrocarbons, Chlorinated; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; D013654:Taurine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; D012964:Sodium; C021974:2-chloropropionic acid