Temporal effects of paraquat/maneb on microglial activation and dopamine neuronal loss in older rats.
We investigated the effects of combined systemic exposure to the herbicide paraquat (PQ) and the fungicide maneb (MB) in 6-month-old rats, an animal model of Parkinson's disease resulting from environmental toxin exposure. Following two doses of PQ (10 mg/kg) and MB (30 mg/kg), 52% of animals developed fatal lung injury. Examination of the remaining animals showed degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta 6 weeks, but not 4 weeks, following PQ/MB. In contrast, microglial activation was observed at 4 weeks, but had abated by 6 weeks. Compared with our previous findings in younger rats, these results suggest increased susceptibility of older animals to lung and brain toxicity from PQ/MB exposure. Microglial activation preceded, and therefore likely contributed to, DA neurodegeneration. Further, electron microscopy revealed an abnormal appearance of the Golgi apparatus at 4 weeks that was confirmed using double immunostaining for tyrosine hydroxylase and Golgi. This suggests that PQ/MB causes protein processing dysfunction in nigral DA neurons that may be either a direct effect of PQ/MB or the result of microglial activation.
Saint-Pierre
Martine
M
Centre de Recherche en Neurosciences, Sainte-Foy, Quebec, Canada.
Tremblay
Marie-Eve
ME
Sik
Attila
A
Gross
Robert E
RE
Cicchetti
Francesca
F
D000375:Aging / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D000818:Animals; D016923:Cell Death / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D008297:Male; D008344:Maneb / Q000008:administration & dosage / Q000633:toxicity*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010269:Paraquat / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004338:Drug Combinations; D008344:Maneb; D010269:Paraquat; D004298:Dopamine