Abstract
BackgroundProlonged inflammation, oxidative stress, and protein aggregation are important factors contributing to Parkinson’s disease (PD) pathology. A known ROS generator, pesticide paraquat (PQ), was indicated as an environmental substance potentially increasing the incidence of PD and is used to model this disease. We investigated if a combination of inflammation and oxidative stress in subthreshold doses would exacerbate the modelled neuropathology.MethodsWe examined the late effects of acute or repeated peripheral inflammation induced by low dose of LPS (10 μg/kg, ip) on PQ toxicity in the rat nigrostriatal dopaminergic pathway, microglial activation markers and expression of major Lewy bodies proteins, α-synuclein and synphilin-1.ResultsWe observed that LPS increased, while PQ decreased body temperature and microglia CD11b expression in the SN. Single LPS pretreatment, 3 h before repeated weekly PQ injections (4×) slightly aggravated neuronal degeneration in the SN. Moreover, degeneration of dopaminergic neurons after weekly repeated inflammation itself (4×) was observed. Interestingly, repeated LPS administration combined with each PQ dose counteracted such effect. The expression of α-synuclein decreased after repeated LPS injections, while only combined, repeated LPS and PQ treatment lowered the levels of synphilin-1. Therefore, α-synuclein and synphilin-1 expression change was influenced by different mechanisms. Concomitantly, decreased levels of the two proteins correlated with decreased degeneration of dopaminergic neurons and with a normalized microglia activation marker.ConclusionsOur results indicate that both oxidative insult triggered by PQ and inflammation caused by peripheral LPS injection can individually induce neurotoxicity. Those factors act through different mechanisms that are not additive and not selective towards dopaminergic neurons, probably implying microglia. Repeated, but small insults from oxidative stress and inflammation when administered in significant time intervals can counteract each other and even act protective as a preconditioning effect. The timing of such repetitive insults is also of essence.
Highlights
Pesticide paraquat (1,1ʹ-dimethyl-4,4ʹ-bipyridinium dichloride, PQ) is used as a model substance to induce oxidative and energetic stress and progressive degeneration of dopaminergic neurons in animals [1,2,3,4,5,6]
Our results indicate that both oxidative insult triggered by PQ and inflammation caused by peripheral LPS injection can individually induce neurotoxicity
We studied the long-term changes, since the literature suggested that the prolonged microglia activation might be the reason of dopaminergic cell degeneration in Parkinson’s disease (PD) [44, 45]
Summary
Pesticide paraquat (1,1ʹ-dimethyl-4,4ʹ-bipyridinium dichloride, PQ) is used as a model substance to induce oxidative and energetic stress and progressive degeneration of dopaminergic neurons in animals [1,2,3,4,5,6]. All the above observations show that inflammatory processes are important in the pathogenesis of PD It is still uncertain whether inflammation is a primary disease mechanism or is triggered by signals from already diseased neurons. These facts led us to investigate whether inflammatory processes combined with oxidative stress would affect the vulnerability of dopaminergic neurons in the SN. Conclusions Our results indicate that both oxidative insult triggered by PQ and inflammation caused by peripheral LPS injection can individually induce neurotoxicity. Those factors act through different mechanisms that are not additive and not selective towards dopaminergic neurons, probably implying microglia.
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