ToxSci Advance Access originally published online on September 8, 2005
Toxicological Sciences 2005 88(2):456-466; doi:10.1093/toxsci/kfi314
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Behavioral and Pathological Effects in the Rat Define Two Groups of Neurotoxic Nitriles
Departament de Ciències Fisiològiques II, Universitat de Barcelona, 08907 Hospitalet de Llobregat, Spain
Received July 21, 2005; accepted September 1, 2005
Adult male Long-Evans rats (250–350 g) received control vehicles, 3,3'-iminodipropionitrile (IDPN, 400 mg kg–1 day–1), allylnitrile (50 mg kg–1 day–1), cis-crotononitrile (110 mg kg–1 day–1), trans-crotononitrile (250 mg kg–1 day–1), or 2,4-hexadienenitrile (300 mg kg–1 day–1), i.p., for 3 consecutive days. Rats treated with IDPN, allylnitrile, and cis-crotononitrile developed the ECC (excitation with circling and choreiform movements) syndrome, whereas those treated with trans-crotononitrile and hexadienenitrile exhibited a different syndrome, characterized by faltering movements. On quantitative analysis, IDPN, allylnitrile, and cis-crotononitrile induced high scores in a test battery for vestibular dysfunction and hyperactivity in the open field, but they did not significantly decrease stride length. Hexadienenitrile and trans-crotononitrile did not increase the vestibular scores or the locomotor activity, but they caused a marked decrease in stride length; they also decreased holding time on a vertical ladder. In brain and spinal cord tissue from rats exposed to IDPN, allylnitrile, or cis-crotononitrile, Fluoro-Jade B, a selective stain for degenerating neurons, did not reveal any labeling other than that of nerve terminals in the glomeruli of the olfactory bulbs, indicating degeneration of the olfactory mucosa. With the same stain, rats exposed to trans-crotononitrile or hexadienenitrile showed a common pattern of selective neurotoxicity; major targets were the inferior olive and the piriform cortex. Hexadienenitrile did not cause hair cell degeneration in the vestibular and auditory sensory epithelia. Present and previous data indicate that neurotoxic nitriles induce one or the other of two different motor syndromes, through either vestibular hair cell degeneration or neuronal degeneration of the inferior olive.
Key Words: iminodipropionitrile; allylnitrile; crotononitrile; hexadienenitrile; vestibular hair cells; inferior olive; motor behavior.
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