Figure 5 - uploaded by Senthilkumar Karuppagounder
Content may be subject to copyright.
Source publication
Parkinson's disease is a progressive neurological disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. It is the most common of the neurodegenerative movement disorders, affecting approximately 1% of the population over age 65. Though the exact cause of the neurodegeneration is unknown, it has been shown that envir...
Contexts in source publication
Context 1
... dysfunction (Fig. 5) has long been thought to play a significant role in depletion of niagral neurons, leading to dopaminergic depletion. Evidence seems to suggest that the neurons in the substantia nigra are particularly prone to mitochondrial energy depletion, which would explain the selective degeneration in this region. The central dopaminergic system ...
Context 2
... to Paraquat and Maneb Just as mitochondrial dysfunction has been strongly implicated in the pathogenesis of Parkinson's disease, there is substantial data implicating oxidative stress (Fig. 5) in its pathogenesis. Brains from patients with Parkinson's disease have shown elevated markers of oxidative damage, indicating that oxidative stress may play a key role in the disease [11,93]. Oxidative species are important in cellular respiration and aid in the regulation of signal transduction pathways. However, they can be ...
Similar publications
Permanent parkinsonism was observed in a man with chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate). Symptoms developed at 37 years of age, two years after exposure had ceased. To our knowledge, this is the second report on parkinsonism associated with exposure to maneb. Manganese is a well-known parkinsonigen toxin i...
Citations
... Therefore, part researchers thought that single exposure of maneb does not easily lead to neurotoxicity in mice. However, epidemiologists have found some interesting data that paraquat and maneb were often used in the same geographical regions, with increased incidence of PD disease (Thrash et al. 2007). Additionally, several human case-control studies and laboratory studies also support an association between maneb, paraquat, and PD. ...
Pesticides are widely used in the world for agriculture and industry. A lot of pesticide residues are observed in our air, soil, and water, which has been regarded as serious environmental contaminations. More and more researches begin to pay attention to the potential toxic effects of pesticides on human health. Till now, it has been confirmed that pesticides exposures are associated with carcinogenicity, neurotoxicity, pulmonotoxicity, reproductive toxicity, developmental toxicity, and metabolic toxicity. Pesticides exposure might play an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. In this review, we focused on the relationship between the main commonly used pesticides and dopaminergic neurodegeneration. The main mechanism of neurotoxicity induced by pesticides exposure were also discussed. Additionally, it is known that the main histological hallmark of dopamine neurodegeneration is the presence of α-synuclein aggregates called Lewy bodies. Therefore, we also discussed the linkages between pesticide exposure and synuclein protein aggregation, which would be helpful to understand the etiology of neurodegeneration.
... It causes neurotoxicity but does not show the significant specificity for the CNS. 127 Ethylene-bis-dithiocarbamate (EBDC) which is a fungicide, also responsible for the induction of ROS, carbonylation of protein, aggregation of α-synuclein due to abnormalities in the functions of proteasomes. 128 Similarly, organophosphates, organochlorines and bipyridyl herbicides have effects on nervous system via production of free radical species and peroxidation of lipids. ...
In this era of technology, neurological disorders are the most prevalent disorders in growing population. Alzheimer's and Parkinson's diseases are the most common neurological disorders which are manifested by any abnormality in the structure and functions of neurons present in brain and spinal cord. Exposure to environmental pollution is a serious issue which is associated with high morbidity and mortality rate in the worldwide. Air pollutants are the major contributors to induce the inflammation in lungs and brain which ultimately impairs the normal functioning of CNS. Air pollution persuades CNS pathology by inducing the oxidative stress, activation of microglial cells, neuroinflammation and alteration in permeability of blood brain barrier. Similarly, exposure of heavy metals also exhibits the major and long-lasting effects on brain and causes cognitive dysfunction. Likewise, pesticides have also major influence on the etiology of neurological disorders. Pesticides such as paraquat and rotenone are involved in the pathogenesis of Parkinson's disease. Treatment strategy for environmental pollutants-induced neurological disorders is a challenging task because conventional therapeutics are effective but do not have optimum therapeutic efficacy against such type of disorders. This article addresses how the environmental pollutants are involved in the pathogenesis of neurological disorders and treatment strategies to reduce the occurrence of neurological disorders.
... Paraquat poorly crosses the blood-brain barrier (BBB) spontaneously as compared to rotenone, hence, it does not inhibit complex I activities; however, paraquat induces the formation of LB in DA neurons in mice and rats [163,164]. It is normally combined with Maneb, an herbicide reported to reduce locomotors activity and SNc neuron loss [165]. Paraquat also kills dopaminergic mesencephalic neurons in the presence of microglia [166]. ...
Parkinson’s disease (PD) has caused most economy to lose their active human capital. Due to poor understanding of the pathophysiology of PD, PD animal models were developed to aid with the investigation of PD pathogenesis and therapy. Currently, the toxin induced and the genetic animal models are being used for most PD research. Most neurotoxin animal model’s studies on PD are focused on the motor features and economic importance associated with dopamine depletion; however, the molecular pathways for cell loss by these models and its usefulness in PD drug development have not been reported fully. In this review, we provided a summary of the toxic mechanism and shortcomings of four neurotoxins (6-OHDA, MPTP, Rotenone and, Paraquat) that are frequently used to mimic PD in animal models. This review will give readers basic knowledge on the best toxin to select for a specific PD experiment and also provide information that will help in development of future toxins with fewer shortcomings. This review also summarizes the mechanism and features of some PD genetic models.
... 26 Results have shown that maneb may, on its own, decrease locomotor activity and produce loss of neurons in the substantia nigra. 29 Chronic exposure to maneb produces signs of manganese intoxication, 30 followed by a neurological syndrome with cognitive, psychiatric, and movement abnormalities that resemble some clinical features of PD. 31 Maneb appears to cross the blood-brain barrier and inhibit mitochondrial complex III. 32,33 The paraquat/maneb model can induce behavioral and motor impairments, significant dopamine-related degeneration, and altered responsiveness to dopamine therapy. ...
Objective:
Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD.
Methods:
We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol.
Results:
Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms.
Conclusions:
Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.
... (induced dopaminergic neuronal damage by TFMPP derivatives was confirmed by the increased lipid peroxidation. Dopaminergic neurotoxins such as MPTP, 6-OHDA and pesticides have shown to selectively inhibit mitochondrial Complex-I, resulting in neuronal death[61,78,79]. Like the other dopaminergic neurotoxins, 2-TFMPP, 3-TFMPP, and 4-TFMPP also selectively inhibited mitochondrial Complex-I activity without affecting the Complex-IV activity. ...
Designer drugs are synthetically formulated to mimic the psychostimulatory effects of an original controlled/illegal drug of abuse. Designer drugs have similar chemical structure or functional analog as compared to existing controlled psychostimulatory drugs. There is a substantial rise in the production and use of designer drugs globally. Piperazine designer drugs were synthesized as an alternative to MDMA and have shown to induce numerous toxic effects leading to huge health, safety, law enforcement & monetary problems, and lethality. Currently, there are very few studies on the dopaminergic neurotoxicity of 1-(3-trifluoromethylphenyl) piperazine (3-TFMPP) and its derivatives (structural congeners). N27 rat dopaminergic neurons are valid cells to investigate the neurotoxic effects and establish the neurotoxic mechanisms of various substances. In the current study, we studied the time and dose-dependent neurotoxicity mechanisms of dopaminergic neurotoxicity of 3-TFMPP (parent compound) and its derivatives (2-TFMPP, 4-TFMPP). TFMPP derivatives-induced significant neurotoxicity (induced dopaminergic neuronal death. TFMPP derivatives-induced oxidative stress, mitochondrial dysfunction, apoptosis and decreased tyrosine hydroxylase expression. If the use of designer drugs are not strictly regulated and restricted around the world, this can lead to numerous central and peripheral disorders leading to a liability to the current and future society.
... Paraquat has been used in conjuction with 2-(dithiocarboxy)aminoethylcarbamodithioato(2-)-kS, kS' manganese also called Maneb, a fungicide, which has been shown to potentiate the effects of both MPTP and Paraquat. Maneb on its own has also been shown to decrease locomotor activity and produce SNc neurons loss (Thrash et al., 2007). ...
Parkinson's disease is one of the most common neurodegenerative diseases. Animal models have contributed a large part to our understanding and therapeutics developed for treatment of PD. There are several more exhaustive reviews of literature that provide the initiated insights into the specific models; however a novel synthesis of the basic advantages and disadvantages of different models is much needed. Here we compare both neurotoxin based and genetic models while suggesting some novel avenues in PD modeling. We also highlight the problems faced and promises of all the mammalian models with the hope of providing a framework for comparison of various systems.
... A major source of these poisons in rural farming areas is insecticides and herbicides, and exposure to these has been suggested as a major risk factor for neurological diseases such as Parkinson's disease [3,4]. One commonly used compound in herbicides is paraquat (PQ), and extensive research has demonstrated a direct link between neurotoxicity and PQ contact [5][6][7]. PQ is a known redox cycling agent that impacts complex I activity of the mitochondria, increases superoxide (O 2 •− ) production, and decreases endogenous antioxidant capacity leading to increased neurotoxicity through apoptosis [8,9]. Several studies have examined the effects of single antioxidant supplementation in the amelioration of PQ-induced neurotoxicity [10][11][12], but to date it remains unclear how combinations of small molecule antioxidants gained through dietary or nutritional means affect this toxinmediated neuron loss. ...
Herbicides containing paraquat may contribute to the pathogenesis of neurodegenerative disorders such as Parkinson’s disease. Paraquat induces reactive oxygen species-mediated apoptosis in neurons, which is a primary mechanism behind its toxicity. We sought to test the effectiveness of a commercially available polyphenol-rich
Aronia melanocarpa
(aronia berry) concentrate in the amelioration of paraquat-induced neurotoxicity. Considering the abundance of antioxidants in aronia berries, we hypothesized that aronia berry concentrate attenuates the paraquat-induced increase in reactive oxygen species and protects against paraquat-mediated neuronal cell death. Using a neuronal cell culture model, we observed that low doses of aronia berry concentrate protected against paraquat-mediated neurotoxicity. Additionally, low doses of the concentrate attenuated the paraquat-induced increase in superoxide, hydrogen peroxide, and oxidized glutathione levels. Interestingly, high doses of aronia berry concentrate increased neuronal superoxide levels independent of paraquat, while at the same time decreasing hydrogen peroxide. Moreover, high-dose aronia berry concentrate potentiated paraquat-induced superoxide production and neuronal cell death. In summary, aronia berry concentrate at low doses restores the homeostatic redox environment of neurons treated with paraquat, while high doses exacerbate the imbalance leading to further cell death. Our findings support that moderate levels of aronia berry concentrate may prevent reactive oxygen species-mediated neurotoxicity.
... For example, combined exposure of PQ with maneb decreases expression of striatum TH, alters states in the dopaminergic neurons transporter, alters motor activity, increases dopamine accumulation in the synaptosome, and alters dopamine levels and metabolites in the striatum. 111 The combined effect of PQ and maneb is evident even among people having residences near fields that have been treated. 112 A particular risk is also identified by exposure to a combination of PQ and maneb when exposed at a younger age. ...
Laboratory studies involving repeated exposure to paraquat (PQ) in different animal models can induce many of the pathological features of Parkinson’s disease (PD), such as the loss of dopaminergic neurons in the nigrostriatal dopamine system. Epidemiological studies identify an increased risk of developing PD in human populations living in areas where PQ exposure is likely to occur and among workers lacking appropriate protective equipment. The mechanisms involved in these phenomena may not be due to any single cause, but rather a multifactorial situation may exist where PQ exposure may cause PD in some circumstances. A multifactorial theory is adopted as we review a number of sub-cellular mechanisms that can explain the observations. The pathogenesis of PD in relation to PQ requires chronic low-dose exposure where PQ acts as an oxidative stress inducer. This paper reviews the consequence PQ oxidative stress and the metabolic processes of PQ inducing excitotoxicity, α-synuclein aggregate formation, autophagy, alteration of dopamine catabolism, and inactivation of tyrosine hydroxylase, which could ultimately cause the loss of dopaminergic cells. The environmental context and biochemistry of PQ in soils, water, and organisms is reviewed to consider potential routes and rates of exposure that might elicit the type of response that is observed in animal models and other types of laboratory research involving PQ exposure. The purpose of this review is to synthesize key relations and summarize hypotheses linking PD to PQ exposure by using multifactorial approach. Recommendations are given to integrate laboratory methods to the environmental context as a means to improve on experimental design. The multifactorial approach is a necessary step for conducting valid tests of causal relations and understanding of potential relations between PD and PQ exposure. This approach may prevent further delay in solving what has proven to be an evasive aetiological problem.
... It is not clear which of these mechanisms may contribute to the toxic effects of specific pesticides in DA neurons and how they may interact (Thrash et al., 2007, Wang et al., 2011. One potential strategy to address these questions is to genetically "mimic" proposed mechanisms of action and determine if this activity is toxic to DA cells. ...
... Among the symptoms of paraquat poisoning, it is relevant to cite the occurrence of intense abdominal pain in clinics [49,50]. The administration of paraquat resulted in a marked and timerelated increase of nociception scores, and pretreatment with SB225002 significantly reduced paraquat-elicited nociception at all evaluated timepoints, displaying an apparent dose-related profile. ...
... Furthermore, the administration of paraquat resulted in worsened performance in beam-walking and footprint paradigms. A series of alterations related to locomotor dysfunction were observed in previous publications dealing with the consequences of paraquat poisoning, mainly via mechanisms involving dopaminergic neurotoxicity [17,35,44,49,51,56]. Concerning the treatment with SB225002, this antagonist presented only partial effects on paraquat-induced motor deficits, although a general improvement of coordination skills was achieved, according to assessment in the beam-walking test or the footprint model. ...
Paraquat (PQ) is an agrochemical agent commonly used worldwide, which is allied to potential risks of intoxication. This herbicide induces the formation of reactive oxygen species (ROS) that ends up compromising various organs, particularly the lungs and the brain. This study evaluated the deleterious effects of paraquat on the central nervous system (CNS) and peripherally, with special attempts to assess the putative protective effects of the selective CXCR2 receptor antagonist SB225002 on these parameters. PQ-toxicity was induced in male Wistar rats, in a total dose of 50 mg/kg, and control animals received saline solution at the same schedule of administration. Separate groups of animals were treated with the selective CXCR2 antagonist SB225002 (1 or 3 mg/kg), administered 30 min before each paraquat injection. The major changes found in paraquat-treated animals were: decreased body weight and hypothermia, nociception behavior, impairment of locomotor and gait capabilities, enhanced TNF-α and IL-1β expression in the striatum, and cell migration to the lungs and blood. Some of these parameters were reversed when the antagonist SB225002 was administered, including recovery of physiological parameters, decreased nociception, improvement of gait abnormalities, modulation of striatal TNF-α and IL-1β expression, and decrease of neutrophil migration to the lungs and blood. Taken together, our results demonstrate that damage to the central and peripheral systems elicited by paraquat can be prevented by the pharmacological inhibition of CXCR2 chemokine receptors. The experimental evidence presented herein extends the comprehension on the toxicodynamic aspects of paraquat, and opens new avenues to treat intoxication induced by this herbicide.
