Effects of alpha-phenyl-tert-butyl nitrone on neuronal survival and motor function following intrastriatal injections of quinolinate or 3-nitropropionic acid.
We have investigated the neuroprotective effects of the the spin-trapping agent alpha-phenyl-tert-butyl nitrone on striatal lesions produced by local injections of the excitotoxin quinolinate or the mitochondrial toxin 3-nitropropionic acid. We have assessed both the behavioural and morphological consequences of the lesion. Thus, we tested paw-reaching ability and amphetamine- and apomorphine-induced rotational behaviour in lesioned rats with or without alpha-phenyl-tert-butyl nitrone treatment, and also explored the relationship between the outcome of the behavioural studies and the extent of the lesion. In the morphological analysis, we chose immunocytochemistry for dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32,000 as a specific marker for striatal neurons. The paw-reaching ability of rats with the quinolinate and 3-nitropropionic acid lesions was significantly impaired compared to normal control animals. Treatment with alpha-phenyl-tert-butyl nitrone significantly ameliorated the paw-reaching deficits produced by the quinolinate lesion, whereas the 3-nitropropionic acid-induced deficits were unaffected by alpha-phenyl-tert-butyl nitrone. Both quinolinate and 3-nitropropionic acid lesions resulted in a rotation asymmetry towards the lesioned side in response to both amphetamine and apomorphine. In the quinolinate lesion model, the alpha-phenyl-tert-butyl nitrone treatment resulted in a less marked motor asymmetry in response to both drugs. By contrast, alpha-phenyl-tert-butyl nitrone did not significantly reduce the drug-induced rotation asymmetry in rats with a 3-nitropropionic acid lesion. Morphological analyses disclosed that alpha-phenyl-tert-butyl nitrone significantly increased the size of the spared striatum in the quinolinate lesions, but only caused a non-significant trend towards an attenuation of the 3-nitropropionic acid lesions. The behavioural deficits were inversely correlated to the size of the spared residual striatum. The intrastriatal injection of 3-nitropropionic acid, unlike the injection of quinolinate, caused degeneration of the nigrostriatal dopamine system as well as of transverse fibre bundles of the internal capsule in the striatum, in addition to the striatal lesion. The behavioural studies revealed that the combination of multiple lesions seen in 3-nitropropionic acid-lesioned rats significantly exacerbated paw-reaching deficits and amphetamine-induced rotation asymmetry. In conclusion, alpha-phenyl-tert-butyl nitrone attenuated behavioural and morphological consequences of striatal lesions induced by local injections of quinolinate, but not of 3-nitropropionic acid. Deficits in behavioural tests of striatal function reflected well the extent of striatal lesion. The intrastriatal injection of 3-nitropropionic acid led to degeneration of both intrinsic striatal neurons and the nigrostriatal dopaminergic system, suggesting that this lesion may provide an animal model of a form of multiple system atrophy rather than Huntington's disease.
Nakao
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Department of Physiology and Neuroscience, University of Lund, Sweden.
Brundin
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D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005260:Female; D007839:Functional Laterality / Q000187:drug effects; D007150:Immunohistochemistry; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009068:Movement / Q000187:drug effects / Q000502:physiology; D017072:Neostriatum / Q000166:cytology* / Q000187:drug effects; D009410:Nerve Degeneration / Q000187:drug effects; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds; D009589:Nitrogen Oxides / Q000494:pharmacology*; D010750:Phosphoproteins; D011422:Propionates / Q000633:toxicity*; D011805:Quinolinic Acids / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects
D003497:Cyclic N-Oxides; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D009589:Nitrogen Oxides; D010750:Phosphoproteins; D011422:Propionates; D011805:Quinolinic Acids; C029217:phenyl-N-tert-butylnitrone; D000661:Amphetamine; D001058:Apomorphine; C015392:3-nitropropionic acid