The influence of preconditioning with low dose of LPS on paraquat-induced neurotoxicity, microglia activation and expression of α-synuclein and synphilin-1 in the dopaminergic system

• Published in: Pharmacological reports Vol. 74; no. 1; pp. 67 - 83
• Main Authors: Kuter, Katarzyna Z., Śmiałowska, Maria, Ossowska, Krystyna
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2022
• Subjects: alpha-Synuclein - metabolism; Animals; Carrier Proteins - metabolism; Disease Models, Animal; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dose-Response Relationship, Drug; Drug Safety and Pharmacovigilance; Environmental Exposure; Herbicides - toxicity; Inflammation - metabolism; Lipopolysaccharides - pharmacology; Medicine; Microglia - drug effects; Microglia - metabolism; Nerve Tissue Proteins - metabolism; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - metabolism; Oxidative Stress - drug effects; Paraquat - toxicity; Parkinson Disease - metabolism; Pharmacotherapy; Pharmacy; Protective Agents - pharmacology; Rats; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Oxidative stress; α-Synuclein; Synphilin-1; Neurodegeneration; Substantia nigra; Pesticides; Paraquat; Midbrain; Inflammation; Ventral tegmental area; Parkinson’s disease; Microglia
• ISSN: 1734-1140; 2299-5684
• DOI: 10.1007/s43440-021-00340-1

Background Prolonged 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. Methods We 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. Results We 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. 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. 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.