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Paraquat and Parkinson's Disease: The Molecular Crosstalk of Upstream Signal Transduction Pathways Leading to Apoptosis

See WZC, Naidu R, Tang KS

Curr Neuropharmacol, 2024;22(1):140-151.
PMID: 36703582 DOI: 10.2174/1570159X21666230126161524

Parkinson's disease (PD) is a heterogeneous disease involving a complex interaction between genes and the environment that affects various cellular pathways and neural networks. Several studies have suggested that environmental factors such as exposure to herbicides, pesticides, heavy metals, and other organic pollutants are significant risk factors for the development of PD. Among the herbicides, paraquat has been commonly used, although it has been banned in many countries due to its acute toxicity. Although the direct causational relationship between paraquat exposure and PD has not been established, paraquat has been demonstrated to cause the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The underlying mechanisms of the dopaminergic lesion are primarily driven by the generation of reactive oxygen species, decrease in antioxidant enzyme levels, neuroinflammation, mitochondrial dysfunction, and ER stress, leading to a cascade of molecular crosstalks that result in the initiation of apoptosis. This review critically analyses the crucial upstream molecular pathways of the apoptotic cascade involved in paraquat neurotoxicity, including mitogenactivated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), and Wnt/β-catenin signaling pathways.

Matched MeSH terms: Paraquat/toxicity
Influence of paraquat on Chrysomya megacephala (Fabricius) (Diptera: Calliphoridae) infesting minced-beef substrates in Kelantan, Malaysia

Mahat NA, Yin CL, Jayaprakash PT

J Forensic Sci, 2014 Mar;59(2):529-32.
PMID: 24745083

This study investigated the influence of paraquat, a prevalent poison used by suicides, on initial oviposition and development of Chrysomya megacephala (Fabricius) using minced-beef substrates. Paraquat in lethal dose for human (40 mg/kg), two times the lethal dose (80 mg/kg) and five times the lethal dose (200 mg/kg) were mixed thoroughly with respective minced-beef substrates (1 kg each) that were decomposed in a shaded habitat fully protected from rain. Results of four replications of the above experiment revealed that the presence of paraquat neither delayed initial oviposition nor prolonged the developmental stages of C. megacephala. Therefore, estimation of postmortem interval (PMI) based on empirical baseline data obtained using animal models devoid of any poisons would still be appropriate for estimating PMI in paraquat-related deaths.

Matched MeSH terms: Paraquat/toxicity*
Fulltext Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

Tang SP, Kuttulebbai Nainamohamed Salam S, Jaafar H, Gan SH, Muzaimi M, Sulaiman SA

Oxid Med Cell Longev, 2017;2017:4605782.
PMID: 28127418 DOI: 10.1155/2017/4605782

Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p < 0.05). The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.

Matched MeSH terms: Paraquat/toxicity*
The effects of metallothionein in paraquat-induced Parkinson disease model of zebrafish

Mohamad Najib NH, Yahaya MF, Das S, Teoh SL

Int J Neurosci, 2023 Dec;133(8):822-833.
PMID: 34623211 DOI: 10.1080/00207454.2021.1990916

INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disease caused by selective degeneration of dopaminergic neurons in the substantia nigra. Metallothionein has been shown to act as a neuroprotectant in various brain injury. Thus, this study aims to identify the effects of full-length human metallothionein 2 peptide (hMT2) in paraquat-induced brain injury in the zebrafish.
METHODOLOGY: A total of 80 adult zebrafish were divided into 4 groups namely control, paraquat-treated, pre-hMT2-treated, and post-hMT2-treated groups. Fish were treated with paraquat intraperitoneally every 3 days for 15 days. hMT2 were injected intracranially on day 0 (pre-treated group) and day 16 (post-treated group). Fish were sacrificed on day 22 and the brains were collected for qPCR, ELISA and immunohistochemistry analysis.
RESULTS: qPCR analysis showed that paraquat treatment down-regulated the expression of genes related to dopamine activity and biosynthesis (dat and th1) and neuroprotective agent (bdnf). Paraquat treatment also up-regulated the expression of the mt2, smtb and proinflammatory genes (il-1α, il-1β, tnf-α and cox-2). hMT2 treatment was able to reverse the effects of paraquat. Lipid peroxidation decreased in the paraquat and pre-hMT2-treated groups. However, lipid peroxidation increased in the post-hMT2-treated group. Paraquat treatment also led to a reduction of dopaminergic neurons while their numbers showed an increase following hMT2 treatment.
CONCLUSION: Paraquat has been identified as one of the pesticides that can cause the death of dopaminergic neurons and affect dopamine biosynthesis. Treatment with exogenous hMT2 could reverse the effects of paraquat in the zebrafish brain.

Matched MeSH terms: Paraquat/toxicity
Pesticide risk assessment: A study on inhalation and dermal exposure to 2,4-D and paraquat among Malaysian paddy farmers

Baharuddin MR, Sahid IB, Noor MA, Sulaiman N, Othman F

J Environ Sci Health B, 2011;46(7):600-7.
PMID: 21749249 DOI: 10.1080/03601234.2011.589309

A cross-section analytical study was conducted to evaluate the risk of pesticide exposure to those applying the Class II pesticides 2,4-D and paraquat in the paddy-growing areas of Kerian, Perak, Malaysia. It investigated the influence of weather on exposure as well as documented health problems commonly related to pesticide exposure. Potential inhalation and dermal exposure for 140 paddy farmers (handlers of pesticides) were assessed. Results showed that while temperature and humidity affected exposure, windspeed had the strongest impact on pesticide exposure via inhalation. However, the degree of exposure to both herbicides via inhalation was below the permissible exposure limits set by United States National Institute of Occupational Safety and Health (NIOSH). Dermal Exposure Assessment Method (DREAM) readings showed that dermal exposure with manual spraying ranged from moderate to high. With motorized sprayers, however, the level of dermal exposure ranged from low to moderate. Dermal exposure was significantly negatively correlated with the usage of protective clothing. Various types of deleterious health effects were detected among users of manual knapsack sprayers. Long-term spraying activities were positively correlated with increasing levels of the gamma-glutamyl transpeptidase (GGT) liver enzyme. The type of spraying equipment, usage of proper protective clothing and adherence to correct spraying practices were found to be the most important factors influencing the degree of pesticide exposure among those applying pesticides.

Matched MeSH terms: Paraquat/toxicity*
Dermal exposure to the herbicide-paraquat results in genotoxic and cytotoxic damage to germ cells in the male rat

D'Souza UJ, Narayana K, Zain A, Raju S, Nizam HM, Noriah O

Folia Morphol (Warsz), 2006 Feb;65(1):6-10.
PMID: 16783728

The effects of exposure to low doses of paraquat, a herbicide, via the dermal route were studied on the spermatozoa of Sprague-Dawley rats. Paraquat (1, 1'-dimethyl-4, 4'-bipyridinium dichloride) was administered once a day for five days, at intervals of 24 h at 0, 6, 15 and 30 mg/kg, and the rats were sacrificed on days 7, 14, 28, and 42 after the last exposure. The sperm suspensions were obtained by mincing the caudae epididymes and ductus deferens for the purpose of performing a sperm morphology test, sperm count and analysis of sperm mortality and sperm motility, as per the standard procedures. The sperm count was decreased (p < 0.05) only on days 7 and 14 but sperm abnormalities increased on all days (p < 0.05). Sperm mortality increased at higher dose-levels (p < 0.05) except on day 42, and motility was affected by 30 mg/kg only on day 42. In conclusion, paraquat is a genotoxic and cytotoxic agent to germ cells in the male rat.

Matched MeSH terms: Paraquat/toxicity*
Neurotoxin-Induced Rodent Models of Parkinson's Disease: Benefits and Drawbacks

El-Gamal M, Salama M, Collins-Praino LE, Baetu I, Fathalla AM, Soliman AM, et al.

Neurotox Res, 2021 Jun;39(3):897-923.
PMID: 33765237 DOI: 10.1007/s12640-021-00356-8

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by cardinal motor impairments, including akinesia and tremor, as well as by a host of non-motor symptoms, including both autonomic and cognitive dysfunction. PD is associated with a death of nigral dopaminergic neurons, as well as the pathological spread of Lewy bodies, consisting predominantly of the misfolded protein alpha-synuclein. To date, only symptomatic treatments, such as levodopa, are available, and trials aiming to cure the disease, or at least halt its progression, have not been successful. Wong et al. (2019) suggested that the lack of effective therapy against neurodegeneration in PD might be attributed to the fact that the molecular mechanisms standing behind the dopaminergic neuronal vulnerability are still a major scientific challenge. Understanding these molecular mechanisms is critical for developing effective therapy. Thirty-five years ago, Calne and William Langston (1983) raised the question of whether biological or environmental factors precipitate the development of PD. In spite of great advances in technology and medicine, this question still lacks a clear answer. Only 5-15% of PD cases are attributed to a genetic mutation, with the majority of cases classified as idiopathic, which could be linked to exposure to environmental contaminants. Rodent models play a crucial role in understanding the risk factors and pathogenesis of PD. Additionally, well-validated rodent models are critical for driving the preclinical development of clinically translatable treatment options. In this review, we discuss the mechanisms, similarities and differences, as well as advantages and limitations of different neurotoxin-induced rat models of PD. In the second part of this review, we will discuss the potential future of neurotoxin-induced models of PD. Finally, we will briefly demonstrate the crucial role of gene-environment interactions in PD and discuss fusion or dual PD models. We argue that these models have the potential to significantly further our understanding of PD.

Matched MeSH terms: Paraquat/toxicity