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Temporal effects of paraquat/maneb on microglial activation and dopamine neuronal loss in older rats
Martine Saint-Pierre1, Marie-Eve Tremblay, Attila Sik
1Centre de Recherche en Neurosciences, Sainte-Foy, Quebec, Canada.
Abstract:
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.
Insights
Older rats exposed to paraquat (PQ) and maneb (MB) herbicides showed increased lung and brain toxicity. This environmental toxin exposure model for Parkinson's disease revealed dopaminergic neuron degeneration and protein processing dysfunction.
Area of Science:
- Environmental toxicology
- Neuroscience
- Pathology
Background:
- Parkinson's disease (PD) is linked to environmental toxin exposure.
- Paraquat (PQ) and maneb (MB) are pesticides linked to PD.
- Older animal models are crucial for understanding age-related disease susceptibility.
Purpose of the Study:
- To investigate the combined effects of PQ and MB on older rats.
- To establish an environmental toxin-induced Parkinson's disease model in aged rats.
- To determine the neurotoxic mechanisms and age-dependent susceptibility.
Main Methods:
- Administered combined PQ and MB to 6-month-old rats.
- Assessed lung injury, dopaminergic (DA) neuron survival in substantia nigra, and microglial activation.
- Utilized electron microscopy and double immunostaining for Golgi apparatus and tyrosine hydroxylase.
Main Results:
- 52% of rats developed fatal lung injury post-exposure.
- DA neuron degeneration in the substantia nigra was observed at 6 weeks, not 4 weeks.
- Microglial activation occurred at 4 weeks, preceding DA neurodegeneration and abating by 6 weeks.
- Abnormal Golgi apparatus appearance and protein processing dysfunction in nigral DA neurons were identified.
Conclusions:
- Older rats exhibit heightened susceptibility to PQ/MB-induced lung and brain toxicity.
- Microglial activation likely contributes to DA neurodegeneration in this model.
- PQ/MB exposure induces protein processing dysfunction in nigral DA neurons, potentially via direct toxicity or neuroinflammation.
