Alpha synuclein (SNCA) genes and environmental factors are important risk factors of Parkinson's disease (PD). The agrichemicals paraquat, maneb and chlorpyrifos selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. We analyzed the ability of low dose paraquat, maneb and chlorpyrifos, separately or combined together, to induce synucleinopathy in wild type mice. Paraquat and maneb applied together did not increase α-Synuclein (α-Syn) levels. By contrast, paraquat and chlorpyrifos together resulted in robust accumulation of α-Syn in striata in mice. Therefore, co-treatment with chlorpyrifos enhanced the effects of paraquat. Paraquat, and its co-treatment with maneb or chlorpyrifos, inhibited all soluble proteasomal expression of 26S proteasome subunits. Both paraquat and chlorpyrifos treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Atg 12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in all the treated animals. These results suggest that a combination of paraquat and chlorpyrifos is much more toxic than paraquat alone or combined with maneb. These effects are likely via inhibitory effects of these toxins on proteasomes and autophagy, which lead to accumulation of α-Syn. Our study provides a novel insight into the mechanisms of action of these agrichemicals.
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Chem Res Toxicol
August 2024
Department of Clinical Analyses, Federal University of Santa Catarina, Florianopolis 88040-900 Santa Catarina, Brazil.
Epidemiological and experimental studies have demonstrated that combined exposure to the pesticides paraquat (PQ) and maneb (MB) increases the risk of developing Parkinson's disease. However, the mechanisms mediating the toxicity induced by combined exposure to these pesticides are not well understood. The aim of this study was to investigate the mechanism(s) of neurotoxicity induced by exposure to the pesticides PQ and MB isolated or in association (PQ + MB) in SH-SY5Y neuroblastoma cells.
View Article and Find Full Text PDFAgeing Res Rev
June 2024
Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran. Electronic address:
Parkinson's disease is predominantly caused by dopaminergic neuron loss in the substantia nigra pars compacta and the accumulation of alpha-synuclein protein. Though the general consensus is that several factors, such as aging, environmental factors, mitochondrial dysfunction, accumulations of neurotoxic alpha-synuclein, malfunctions of the lysosomal and proteasomal protein degradation systems, oxidative stress, and neuroinflammation, are involved in the neurodegeneration process of Parkinson's disease, the precise mechanism by which all of these factors are triggered remains unknown. Typically, neurotoxic compounds such as rotenone, 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl 4-phenyl pyridinium (mpp), paraquat, and maneb are used to Preclinical models of Parkinson's disease Ferulic acid is often referred to by its scientific name, 4-hydroxy-3-methoxycinnamic acid (C10H10O4), and is found naturally in cereals, fruits, vegetables, and bee products.
View Article and Find Full Text PDFACS Chem Neurosci
June 2023
Neuroscience Research Team, Institute of Medical Investigations, Faculty of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Torre 1, Laboratorio 412, Medellín 050010, Colombia.
Parkinson's disease (PD), a progressive neurodegenerative movement disorder, has reached pandemic status worldwide. This neurologic disorder is caused primarily by the specific deterioration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). Unfortunately, there are no therapeutic agents that slow or delay the disease progression.
View Article and Find Full Text PDFJ Neuroinflammation
February 2023
National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, 116044, China.
Introduction: The mechanisms of cognitive impairments in Parkinson's disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by microglial cells contributes to cognitive deficits in neuropathological conditions and macrophage antigen complex-1 (Mac1) is a key factor in controlling microglial activation.
Objectives: To explore whether Mac1-mediated microglial activation participates in cognitive dysfunction in PD using paraquat and maneb-generated mouse PD model.
Pestic Biochem Physiol
October 2022
Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow 226 001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India. Electronic address:
Overproduction of free radicals and inflammation could lead to maneb (MB)- and paraquat (PQ)-induced toxicity in the polymorphonuclear leukocytes (PMNs). Cyclooxygenase-2 (COX-2), an inducible COX, is imperative in the pesticides-induced pathological alterations. However, its role in MB- and PQ-induced toxicity in the PMNs is not yet clearly deciphered.
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