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Folia Neuropathologica 2019Rotenone ([2R-(2α,6aα,12aα)]-1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-[1]benzopyran[3,4-b]furo [2,3-h][1]benzopyran-6(6aH)-one) is a naturally... (Review)
Review
Rotenone ([2R-(2α,6aα,12aα)]-1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-[1]benzopyran[3,4-b]furo [2,3-h][1]benzopyran-6(6aH)-one) is a naturally occurring compound derived from the roots and stems of Derris, Tephrosia, Lonchocarpus and Mundulea plant species. Since its discovery at the end of the 19th century, rotenone has been widely used as a pesticide for controlling insects, ticks and lice, and as a piscicide for management of nuisance fish in lakes and reservoirs. In 2000, Betarbet et al. reproduced most of the behavioural, biochemical and pathological features of Parkinson's disease (PD) in rotenone-treated rats. Since that time, rotenone has received much attention as it would be one of the environmental neurotoxins implicated in etiopathogenesis of PD. Moreover, it represents a common experimental model to investigate the underlying mechanisms leading to PD and evaluate the new potential therapies for the disease. In the current general review, we aimed to address recent advances in the hazards of the environmental applications of rotenone and discuss the updates on the rotenone model of PD and whether it is implicated in the etiopathogenesis of the disease.
Topics: Animals; Cell Death; Disease Models, Animal; Humans; Inflammation; Parkinson Disease; Reactive Oxygen Species; Rotenone
PubMed: 32337944
DOI: 10.5114/fn.2019.89857 -
Chemical Research in Toxicology May 2021Rotenone is a naturally occurring toxin that inhibits complex I of the mitochondrial electron transport chain. Several epidemiological studies have shown an increased... (Review)
Review
Rotenone is a naturally occurring toxin that inhibits complex I of the mitochondrial electron transport chain. Several epidemiological studies have shown an increased risk of Parkinson's disease (PD) in individuals exposed chronically to rotenone, and it has received great attention for its ability to reproduce many critical features of PD in animal models. Laboratory studies of rotenone have repeatedly shown that it induces in vivo substantia nigra dopaminergic cell loss, a hallmark of PD neuropathology. Additionally, rotenone induces in vivo aggregation of α-synuclein, the major component of Lewy bodies and Lewy neurites found in the brain of PD patients and another hallmark of PD neuropathology. Some in vivo rotenone models also reproduce peripheral signs of PD, such as reduced intestinal motility and peripheral α-synuclein aggregation, both of which are thought to precede classical signs of PD in humans, such as cogwheel rigidity, bradykinesia, and resting tremor. Nevertheless, variability has been noted in cohorts of animals exposed to the same rotenone exposure regimen and also between cohorts exposed to similar doses of rotenone. Low doses, administered chronically, may reproduce PD symptoms and neuropathology more faithfully than excessively high doses, but overlap between toxicity and parkinsonian motor phenotypes makes it difficult to separate if behavior is examined in isolation. Rotenone degrades when exposed to light or water, and choice of vehicle may affect outcome. Rotenone is metabolized extensively in vivo, and choice of route of exposure influences greatly the dose used. However, male rodents may be capable of greater metabolism of rotenone, which could therefore reduce their total body exposure when compared with female rodents. The pharmacokinetics of rotenone has been studied extensively, over many decades. Here, we review these pharmacokinetics and models of PD using this important piscicide.
Topics: Animals; Disease Models, Animal; Electron Transport Complex I; Mice; Parkinson Disease; Rotenone
PubMed: 33961406
DOI: 10.1021/acs.chemrestox.0c00522 -
PloS One 2022Rotenone is a commonly used insecticidal chemical in agriculture and it is an inhibitor of mitochondrial complex Ⅰ. Previous studies have found that rotenone induces...
Rotenone is a commonly used insecticidal chemical in agriculture and it is an inhibitor of mitochondrial complex Ⅰ. Previous studies have found that rotenone induces the production of reactive oxygen species (ROS) by inhibiting electron transport in the mitochondria of somatic and germ cells. However, there is little precise information on the effects of rotenone exposure in porcine oocytes during in vitro maturation, and the mechanisms underlying these effects have not been determined. The Cumulus-oocyte complexes were supplemented with different concentrations of rotenone to elucidate the effects of rotenone exposure on the meiotic maturation of porcine oocytes during in vitro maturation for about 48 hours. First, we found that the maturation rate and expansion of cumulus cells were significantly reduced in the 3 and 5 μM rotenone-treated groups. Subsequently, the concentration of rotenone was determined to be 3 μM. Also, immunofluorescence, western blotting, and image quantification analyses were performed to test the rotenone exposure on the meiotic maturation, total and mitochondrial ROS, mitochondrial function and biogenesis, mitophagy and apoptosis in porcine oocytes. Further experiments showed that rotenone treatment induced mitochondrial dysfunction and failure of mitochondrial biogenesis by repressing the level of SIRT1 during in vitro maturation of porcine oocytes. In addition, rotenone treatment reduced the ratio of active mitochondria to total mitochondria, increased ROS production, and decreased ATP production. The levels of LC3 and active-caspase 3 were significantly increased by rotenone treatment, indicating that mitochondrial dysfunction induced by rotenone increased mitophagy but eventually led to apoptosis. Collectively, these results suggest that rotenone interferes with porcine oocyte maturation by inhibiting mitochondrial function.
Topics: Swine; Animals; Female; Rotenone; Reactive Oxygen Species; Oocytes; Cumulus Cells; Mitochondria
PubMed: 36441709
DOI: 10.1371/journal.pone.0277477 -
Environmental Toxicology and... Jul 2022Rotenone (ROT) is a widely used natural pesticide, and its effect on growth and developmental toxicity remain unclear. In the present study, the effects of ROT exposure...
Rotenone (ROT) is a widely used natural pesticide, and its effect on growth and developmental toxicity remain unclear. In the present study, the effects of ROT exposure on the reproductive structure and function of the female Drosophila melanogaster and third instar larvae were investigated. ROT exposure on female Drosophila melanogaster resulted in developmental inhibition and ovarian abnormality, which were evident from the disruptive growth of border cells as well as morphological changes in the orientation of nurse cells during the 9th-10th stage of developing egg chamber of in the Drosophila ovary. Other abnormalities, such as, altered developmental gene expression (Osk, Grk, Nos, Bic-d), inhibition in the kinesin motor protein level (KIF-5B), increased caspases activities (Caspase 3, 8, & 9) and apoptosis were also observed. Subsequently, ROT treated larvae exhibited behavioral deficits and delay in developmental time. The above findings demonstrate that the exposure of ROT causes developmental toxicity in Drosophila melanogaster.
Topics: Animals; Antioxidants; Caspases; Drosophila Proteins; Drosophila melanogaster; Female; Larva; Plant Extracts; Rotenone
PubMed: 35654372
DOI: 10.1016/j.etap.2022.103892 -
Journal of Biochemical and Molecular... Dec 2020Rotenone is a widely used organic pesticide; its serious side effect for off-target species is neurotoxicity. The primary mechanism of rotenone toxicity is inhibition of... (Review)
Review
Rotenone is a widely used organic pesticide; its serious side effect for off-target species is neurotoxicity. The primary mechanism of rotenone toxicity is inhibition of the mitochondrial complex I. Oxidative stress, apoptosis, and reduction of autophagy are key outcomes of the inhibition of complex I. Numerous in vitro and in vivo studies have shown antioxidant, anti-apoptotic, and autophagy enhancement of a variety of natural compounds (NCs). In this manuscript, we reviewed several NCs, which have protective effects against rotenone-induced neurotoxicity.
Topics: Animals; Biological Products; Nervous System; Rotenone
PubMed: 32830361
DOI: 10.1002/jbt.22605 -
Biochimica Et Biophysica Acta.... Mar 2023Rotenone has widespread beneficial effects in agriculture, fisheries and animal husbandries; however prolonged exposure causes a detrimental effect on the health of...
Rotenone has widespread beneficial effects in agriculture, fisheries and animal husbandries; however prolonged exposure causes a detrimental effect on the health of personnel working in such industries. Rotenone during its extraction, formulation or usage may cross the blood brain barrier leading to neurodegeneration and the development of Parkinson's disease like symptoms. It is a known inhibitor of the mitochondrial ETC complex I and responsible for impairing the OXPHOS system. Our study showed that rotenone exposure results in an increased production of ROS and decreased ATP level along with a conspicuous loss of mitochondrial membrane potential in N2A cells. The transcription and expression pattern of cofilin, a key component of actin cytoskeleton, was also altered after rotenone exposure; leading to the actin cytoskeleton degradation. We further observed an increased expression, as well as activity of matrix metalloproteinase9 (MMP9) in rotenone exposed N2A cells; suggesting the involvement of inflammation upon rotenone exposure. Simultaneously, an opposite pattern was noticed for the tissue inhibitors of metalloproteinases-1 (TIMP-1) protein, which is a known modulator of MMP9 activity. Additionally, the localization of MMP9 along with alpha-synuclein, UCHL1 and cofilin suggested their close proximity and cross interaction upon rotenone treatment. Furthermore, we observed significant increase in the level of TNF-α upon rotenone exposure along with the phosphorylation of RIPK1, RIPK3 and MLKL that has been identified as the necroptosis markers leading to programmed necroptotic death.
Topics: Animals; Rotenone; Protein Kinases; Necroptosis; Matrix Metalloproteinase 9; Cytoskeleton
PubMed: 36581087
DOI: 10.1016/j.bbamcr.2022.119417 -
Molecular Biology Reports Feb 2023Several results demonstrated that microglia and peripheral monocytes/macrophages infiltrating the central nervous system (CNS) are involved in cell response against...
BACKGROUND
Several results demonstrated that microglia and peripheral monocytes/macrophages infiltrating the central nervous system (CNS) are involved in cell response against toxic compounds. It has been shown that rotenone induces neurodegeneration in various in vitro experimental models. Baicalin, a natural compound, is able to attenuate cell damage through anti-oxidant, anti-microbial, anti-inflammatory, and immunomodulatory action. Using THP-1 monocytes, we investigated rotenone effects on mitochondrial dysfunction and apoptosis, as well as baicalin ability to counteract rotenone toxicity.
METHODS AND RESULTS
THP-1 cells were exposed to rotenone (250 nM), in the presence/absence of baicalin (10-500 μM) for 2-24 h. Reactive Oxygen Species production (ROS), mitochondrial activity and transmembrane potential (Δψm), DNA damage, and caspase-3 activity were assessed. Moreover, gene expression of mitochondrial transcription factor a (mtTFA), interleukin-1β (IL-1β), B-cell lymphoma 2 (Bcl2) and BCL2-associated X protein (Bax), together with apoptotic morphological changes, were evaluated. After 2 h of rotenone incubation, increased ROS production and altered Δψm were observed, hours later resulting in DNA oxidative damage and apoptosis. Baicalin treatment at 50 µM counteracted rotenone toxicity by modulating the expression levels of some proteins involved in mitochondrial biogenesis and apoptosis. Interestingly, at higher baicalin concentrations, rotenone-induced alterations persisted.
CONCLUSIONS
These results give evidence that exposure to rotenone may promote the activation of THP-1 monocytes contributing to enhanced neurodegeneration. In this context, baicalin at low concentration exerts beneficial effects on mitochondrial function, and thus may prevent the onset of neurotoxic processes.
Topics: Humans; Rotenone; Reactive Oxygen Species; THP-1 Cells; Oxidative Stress; Apoptosis; Anti-Inflammatory Agents
PubMed: 36446982
DOI: 10.1007/s11033-022-08060-2 -
Journal of Environmental Pathology and... 1978The chemistry, biotransformation, pharmacology, toxicology, and carcinogenicity of rotenone have been reviewed. Further investigation of the biotransformation pathways... (Review)
Review
The chemistry, biotransformation, pharmacology, toxicology, and carcinogenicity of rotenone have been reviewed. Further investigation of the biotransformation pathways of rotenone and other rotenoids should be undertaken. The acute and chronic toxicology, particularly at low concentration, should be determined in order to develop toxicity rating for this class of chemicals. A mutagenic study utilizing all presently available methods would add further knowledge concerning sites of action. More information is required to properly evaluate the hazards to humans from rotenone and other rotenoids. Carcinogenic studies at low concentrations with large groups of rodents must be undertaken to settle the present dilemma of carcinogenicity vs. non-carcinogenicity. Moreover, an epidemiological study of exposed workers might develop information concerning the toxicology of rotenone as well as its possible carcinogenicity to humans.
Topics: Animals; Carcinogens; Chemical Phenomena; Chemistry; Humans; Rotenone
PubMed: 363963
DOI: No ID Found -
International Journal of Molecular... Apr 2022Reactive oxygen species (ROS) cause oxidative stress by generating reactive aldehydes known as 4-hydroxynonenal (4-HNE). 4-HNE modifies protein via covalent adduction;...
Reactive oxygen species (ROS) cause oxidative stress by generating reactive aldehydes known as 4-hydroxynonenal (4-HNE). 4-HNE modifies protein via covalent adduction; however, little is known about the degradation mechanism of 4-HNE-adducted proteins. Autophagy is a dynamic process that maintains cellular homeostasis by removing damaged organelles and proteins. In this study, we determined the role of a superoxide dismutase (SOD) mimetic MnTnBuOE-2-PyP (MnP, BMX-001) on rotenone-induced 4-HNE aggresome degradation in HL-1 cardiomyocytes. A rotenone treatment (500 nM) given for 24 h demonstrated both increased ROS and 4-HNE aggresome accumulation in HL-1 cardiomyocytes. In addition, cardiomyocytes treated with rotenone displayed an increase in the autophagy marker LC3-II, as shown by immunoblotting and immunofluorescence. A pre-treatment with MnP (20 µM) for 24 h attenuated rotenone-induced ROS formation. An MnP pre-treatment showed decreased 4-HNE aggresomes and LC3-II formation. A rotenone-induced increase in autophagosomes was attenuated by a pre-treatment with MnP, as shown by fluorescent-tagged LC3 (tfLC3). Rotenone increased tubulin hyperacetylation through the ROS-mediated pathway, which was attenuated by MnP. The disruption of autophagy caused HL-1 cell death because a 3-methyladenine inhibitor of autophagosomes caused reduced cell death. Yet, rapamycin, an inducer of autophagy, increased cell death. These results indicated that a pre-treatment with MnP decreased rotenone-induced 4-HNE aggresomes by enhancing the degradation process.
Topics: Autophagosomes; Autophagy; Myocytes, Cardiac; Reactive Oxygen Species; Rotenone
PubMed: 35563066
DOI: 10.3390/ijms23094675 -
Chemosphere Mar 2022Rotenone is a neurotoxic pesticide widely used in agriculture. Dopaminergic neuron has long been considered as the target of rotenone. We recently reported that rotenone...
Rotenone is a neurotoxic pesticide widely used in agriculture. Dopaminergic neuron has long been considered as the target of rotenone. We recently reported that rotenone exposure also resulted in hippocampal and cortical neurodegeneration and cognitive dysfunction in mice. However, the mechanisms remain unknown. Here, we elucidated whether blood brain barrier (BBB) disruption and subsequent neuronal apoptosis mediated by microglial activation were involved in rotenone-elicited cognitive impairments. Results showed that rotenone dose-dependently elevated evens blue extravasation, fibrinogen accumulation and reduced expressions of tight junction proteins in the hippocampus and cortex of mice. Interestingly, microglial depletion and inactivation by PLX3397 and minocycline, respectively, markedly attenuated rotenone-elicited increase of BBB permeability, indicating a critical role of microglia. Furthermore, microglial depletion and inactivation were shown to abrogate rotenone-induced activation of matrix metalloproteinases 2 and 9 (MMP-2/-9), two important factors to regulate tight junction degradation and BBB permeability, in mice. Moreover, SB-3CT, a widely used MMP-2/-9 inhibitor, increased BBB integrity and simultaneously elevated expressions of tight junction proteins in rotenone-intoxicated mice. Finally, we found that SB-3CT significantly mitigated rotenone-induced neuronal apoptosis and synaptic loss as well as learning and memory impairments in mice. Altogether, this study revealed that rotenone elicited cognitive impairments in mice through microglia-mediated BBB disruption and neuronal apoptosis via MMP-2/-9, providing a novel aspect for the pathogenesis of pesticide-induced neurotoxicity and Parkinson's disease (PD)-related dementia.
Topics: Animals; Apoptosis; Blood-Brain Barrier; Dopaminergic Neurons; Mice; Microglia; Rotenone
PubMed: 34822863
DOI: 10.1016/j.chemosphere.2021.132982