The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Zhengui Xia - One of the best experts on this subject based on the ideXlab platform.
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jnk inhibition of vmat2 contributes to Rotenone induced oxidative stress and dopamine neuron death
Toxicology, 2015Co-Authors: Won Seok Choi, Hyungwook Kim, Zhengui XiaAbstract:Treatment with Rotenone, both in vitro and in vivo, is widely used to model dopamine neuron death in Parkinson’s disease upon exposure to environmental neurotoxicants and pesticides. Mechanisms underlying Rotenone neurotoxicity are still being defined. Our recent studies suggest that Rotenone-induced dopamine neuron death involves microtubule destabilization, which leads to accumulation of cytosolic dopamine and consequently reactive oxygen species (ROS). Furthermore, the c-Jun N-terminal protein kinase (JNK) is required for Rotenone-induced dopamine neuron death. Here we report that the neural specific JNK3 isoform of the JNKs, but not JNK1 or JNK2, is responsible for this neuron death in primary cultured dopamine neurons. Treatment with taxol, a microtubule stabilizing agent, attenuates Rotenone-induced phosphorylation and presumably activation of JNK. This suggests that JNK is activated by microtubule destabilization upon Rotenone exposure. Moreover, Rotenone inhibits VMAT2 activity but not VMAT2 protein levels. Significantly, treatment with SP600125, a pharmacological inhibitor of JNKs, attenuates Rotenone inhibition of VMAT2. Furthermore, decreased VMAT2 activity following in vitro incubation of recombinant JNK3 protein with purified mesencephalic synaptic vesicles suggests that JNK3 can inhibit VMAT2 activity. Together with our previous findings, these results suggest that Rotenone induces dopamine neuron death through a series of sequential events including microtubule destabilization, JNK3 activation, VMAT2 inhibition, accumulation of cytosolic dopamine, and generation of ROS. Our data identify JNK3 as a novel regulator of VMAT2 activity.
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basic fibroblast growth factor protects against Rotenone induced dopaminergic cell death through activation of extracellular signal regulated kinases 1 2 and phosphatidylinositol 3 kinase pathways
The Journal of Neuroscience, 2006Co-Authors: Shihling Hsuan, Heather M Klintworth, Zhengui XiaAbstract:Administration of Rotenone to rats reproduces many features of Parkinson’s disease, including dopaminergic neuron degeneration, and provides a useful model to study the pathogenesis of Parkinson’s disease. However, the cell death mechanisms induced by Rotenone and potential neuroprotective mechanisms against Rotenone are not well defined. Here we report that Rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells is attenuated by pretreatment with several growth factors, most notably basic fibroblast growth factor (bFGF). bFGF activated both extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3-kinase) pathways in SH-SY5Y cells. Ectopic activation of ERK1/2 or PI3-kinase protected against Rotenone, whereas inhibition of either pathway attenuated bFGF protection. Reducing the expression of the proapoptotic protein Bcl-2-associated death protein (BAD) by small interfering RNA rendered SH-SY5Y cells resistant to Rotenone, implicating BAD in Rotenone-induced cell death. Interestingly, bFGF induced a long-lasting phosphorylation of BAD at serine 112, suggesting BAD inactivation through the ERK1/2 signaling pathway. Moreover, primary cultured dopaminergic neurons from mesencephalon were more sensitive to Rotenone-induced cell death than nondopaminergic neurons in the same culture. The loss of dopaminergic neurons was blocked by bFGF, an inhibition dependent on ERK1/2 and PI3-kinase signaling. These data suggest that Rotenone-induced dopaminergic cell death requires BAD and identify bFGF and its activation of ERK1/2 and PI3-kinase signaling pathways as novel intervention strategies to block cell death in the Rotenone model of Parkinson’s disease.
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Rotenone induced apoptosis is mediated by p38 and jnk map kinases in human dopaminergic sh sy5y cells
Toxicological Sciences, 2004Co-Authors: Kathleen Newhouse, Shihling Hsuan, Sandra H Chang, Beibei Cai, Yupeng Wang, Zhengui XiaAbstract:Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson's disease in animal models. Though Rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of Rotenone-induced neuronal cell death. Our results suggest that Rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, Rotenone treatment induces phosphorylation of c-Jun, the c-Jun N-terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated Rotenone-induced apoptosis. These data suggest that Rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases and caspases. These studies provide insights concerning the molecular mechanisms of Rotenone-induced apoptosis in neuronal cells.
Saida Haider - One of the best experts on this subject based on the ideXlab platform.
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curcumin restores Rotenone induced depressive like symptoms in animal model of neurotoxicity assessment by social interaction test and sucrose preference test
Metabolic Brain Disease, 2019Co-Authors: Syeda Madiha, Saida HaiderAbstract:Environmental toxin Rotenone has been associated to with increased Parkinson's disease (PD) prevalence in population. Depression is one of the main non-motor symptoms of PD. Curcumin exhibits neuroprotective action in neurodegenerative diseases. In the study we investigated the effect of pre- and post-treatment of curcumin on Rotenone-induced depressive-like behaviors and neurotransmitter alterations in rat model of PD. In pre-treatment phase rats were administered with curcumin (100 mg/kg/day, p.o.) for 2 weeks. After curcumin treatment Rotenone (1.5 mg/kg/day, s.c.) was administered in Pre-Cur + Rot group and Rotenone alone group for 8 days. Meanwhile, in Post-Cur + Rot group Rotenone was injected for 8 days in order to develop PD-like symptoms. After Rotenone administration curcumin (100 mg/kg/day, p.o.) was administered in Post-Cur + Rot group for 2 weeks. Depressive-like behaviors were monitored by the forced swim test (FST), open field test (OFT), sucrose preference test (SPT) and social interaction test (SIT). Animals were decapitated after behavioral analysis, striatum and hippocampus were dissected out for neurochemical estimations. Results showed that the Rotenone administration significantly (p < 0.01) produced depressive-like symptoms in all depression-related behavioral test. All these behavioral deficits were accompanied by the reduction of striatal and hippocampal neurotransmitter levels following Rotenone administration. Pre- and post-treatment with curcumin significantly (p < 0.01) reversed the depressive-like behavior induced by Rotenone and significantly (p < 0.01) improved neurotransmitter levels as compared to Rotenone injected rats. Our results strongly suggest that normalization of neurotransmitter levels particularly highlights the antidepressant effect of curcumin against Rotenone-induced depressive behavior.
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Curcumin restores Rotenone induced depressive-like symptoms in animal model of neurotoxicity: assessment by social interaction test and sucrose preference test
Metabolic Brain Disease, 2018Co-Authors: Syeda Madiha, Saida HaiderAbstract:Environmental toxin Rotenone has been associated to with increased Parkinson’s disease (PD) prevalence in population. Depression is one of the main non-motor symptoms of PD. Curcumin exhibits neuroprotective action in neurodegenerative diseases. In the study we investigated the effect of pre- and post-treatment of curcumin on Rotenone-induced depressive-like behaviors and neurotransmitter alterations in rat model of PD. In pre-treatment phase rats were administered with curcumin (100 mg/kg/day, p.o.) for 2 weeks. After curcumin treatment Rotenone (1.5 mg/kg/day, s.c.) was administered in Pre-Cur + Rot group and Rotenone alone group for 8 days. Meanwhile, in Post-Cur + Rot group Rotenone was injected for 8 days in order to develop PD-like symptoms. After Rotenone administration curcumin (100 mg/kg/day, p.o.) was administered in Post-Cur + Rot group for 2 weeks. Depressive-like behaviors were monitored by the forced swim test (FST), open field test (OFT), sucrose preference test (SPT) and social interaction test (SIT). Animals were decapitated after behavioral analysis, striatum and hippocampus were dissected out for neurochemical estimations. Results showed that the Rotenone administration significantly (p
Syeda Madiha - One of the best experts on this subject based on the ideXlab platform.
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curcumin restores Rotenone induced depressive like symptoms in animal model of neurotoxicity assessment by social interaction test and sucrose preference test
Metabolic Brain Disease, 2019Co-Authors: Syeda Madiha, Saida HaiderAbstract:Environmental toxin Rotenone has been associated to with increased Parkinson's disease (PD) prevalence in population. Depression is one of the main non-motor symptoms of PD. Curcumin exhibits neuroprotective action in neurodegenerative diseases. In the study we investigated the effect of pre- and post-treatment of curcumin on Rotenone-induced depressive-like behaviors and neurotransmitter alterations in rat model of PD. In pre-treatment phase rats were administered with curcumin (100 mg/kg/day, p.o.) for 2 weeks. After curcumin treatment Rotenone (1.5 mg/kg/day, s.c.) was administered in Pre-Cur + Rot group and Rotenone alone group for 8 days. Meanwhile, in Post-Cur + Rot group Rotenone was injected for 8 days in order to develop PD-like symptoms. After Rotenone administration curcumin (100 mg/kg/day, p.o.) was administered in Post-Cur + Rot group for 2 weeks. Depressive-like behaviors were monitored by the forced swim test (FST), open field test (OFT), sucrose preference test (SPT) and social interaction test (SIT). Animals were decapitated after behavioral analysis, striatum and hippocampus were dissected out for neurochemical estimations. Results showed that the Rotenone administration significantly (p < 0.01) produced depressive-like symptoms in all depression-related behavioral test. All these behavioral deficits were accompanied by the reduction of striatal and hippocampal neurotransmitter levels following Rotenone administration. Pre- and post-treatment with curcumin significantly (p < 0.01) reversed the depressive-like behavior induced by Rotenone and significantly (p < 0.01) improved neurotransmitter levels as compared to Rotenone injected rats. Our results strongly suggest that normalization of neurotransmitter levels particularly highlights the antidepressant effect of curcumin against Rotenone-induced depressive behavior.
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Curcumin restores Rotenone induced depressive-like symptoms in animal model of neurotoxicity: assessment by social interaction test and sucrose preference test
Metabolic Brain Disease, 2018Co-Authors: Syeda Madiha, Saida HaiderAbstract:Environmental toxin Rotenone has been associated to with increased Parkinson’s disease (PD) prevalence in population. Depression is one of the main non-motor symptoms of PD. Curcumin exhibits neuroprotective action in neurodegenerative diseases. In the study we investigated the effect of pre- and post-treatment of curcumin on Rotenone-induced depressive-like behaviors and neurotransmitter alterations in rat model of PD. In pre-treatment phase rats were administered with curcumin (100 mg/kg/day, p.o.) for 2 weeks. After curcumin treatment Rotenone (1.5 mg/kg/day, s.c.) was administered in Pre-Cur + Rot group and Rotenone alone group for 8 days. Meanwhile, in Post-Cur + Rot group Rotenone was injected for 8 days in order to develop PD-like symptoms. After Rotenone administration curcumin (100 mg/kg/day, p.o.) was administered in Post-Cur + Rot group for 2 weeks. Depressive-like behaviors were monitored by the forced swim test (FST), open field test (OFT), sucrose preference test (SPT) and social interaction test (SIT). Animals were decapitated after behavioral analysis, striatum and hippocampus were dissected out for neurochemical estimations. Results showed that the Rotenone administration significantly (p
Rajamurugan Ramachandran - One of the best experts on this subject based on the ideXlab platform.
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Fisetin protects against Rotenone-induced neurotoxicity through signaling pathway.
Frontiers in Bioscience, 2019Co-Authors: Malathi Rajendran, Rajamurugan RamachandranAbstract:The present study was designed to evaluate the protective effect of fisetin against Rotenone induced toxicity in SH-SY5Y neuroblastoma cellular model of Parkinson's disease (PD). SH-SY5Y neuroblastoma cells were treated with fisetin (5µM) 2 hr prior to being treated with Rotenone (100 nM). Following the exposure of SH-SY5Y cells to Rotenone, there was marked decreased cell viability, increased oxidative stress, activation of caspase-3 and apoptosis (dual staining, expressions of pro-apoptotic and anti-apoptotic indices). However pretreatment with fisetin significantly and dose-dependently alleviated Rotenone induced cytotoxicity and oxidative stress in SH-SY5Y cells. Moreover, fisetin attenuated Rotenone induced toxicity by down-regulating Bax, caspases-3 protein expression and up-regulating protein expression of Bcl-2, p38/JNK-MAPK and PI3K, Akt, GSK-3β pathways. Collectively, these results suggest that fisetin could prevent the Rotenone-induced neurotoxicity via various signaling pathways.
Jaushyong Hong - One of the best experts on this subject based on the ideXlab platform.
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microglial activation contributes to cognitive impairments in Rotenone induced mouse parkinson s disease model
Journal of Neuroinflammation, 2021Co-Authors: Dongdong Zhang, Liyan Hou, Lu Jing, Zhengzheng Ruan, Bingjie Peng, Xiaomeng Zhang, Jaushyong Hong, Jie Zhao, Qingshan WangAbstract:Background Cognitive decline occurs frequently in Parkinson's disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using a Rotenone-induced mouse PD model. Methods To evaluate the role of microglia in Rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by Morris water maze, objective recognition, and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation, and apoptosis were determined by immunohistochemistry and Western blot or immunofluorescence staining. The gene expression of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. Results Rotenone dose-dependently induced cognitive deficits in mice by showing decreased performance of Rotenone-treated mice in the novel objective recognition, passive avoidance, and Morris water maze compared with that of vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, and Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. A time course experiment revealed that Rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in Rotenone-injected mice. Mechanistically, PLX3397 and minocycline attenuated Rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in mice treated with combined PLX3397 or minocycline and Rotenonee compared with Rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate Rotenone-induced neuronal apoptosis. Conclusions Taken together, our findings suggested that microglial activation contributes to cognitive impairments in a Rotenone-induced mouse PD model via neuroinflammation, oxidative stress, and apoptosis, providing novel insight into the immunopathogensis of cognitive deficits in PD.
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Rotenone activates phagocyte nadph oxidase by binding to its membrane subunit gp91phox
Free Radical Biology and Medicine, 2012Co-Authors: Hui Zhou, Jaushyong Hong, Feng Zhang, Shih Heng Chen, Dan Zhang, Belinda Wilson, Huiming GaoAbstract:Abstract Rotenone, a widely used pesticide, reproduces parkinsonism in rodents and associates with increased risk for Parkinson disease. We previously reported that Rotenone increased superoxide production by stimulating the microglial phagocyte NADPH oxidase (PHOX). This study identified a novel mechanism by which Rotenone activates PHOX. Ligand-binding assay revealed that Rotenone directly bound to membrane gp91phox, the catalytic subunit of PHOX; such binding was inhibited by diphenyleneiodonium, a PHOX inhibitor with a binding site on gp91phox. Functional studies showed that both membrane and cytosolic subunits were required for Rotenone-induced superoxide production in cell-free systems, intact phagocytes, and COS7 cells transfected with membrane subunits (gp91phox/p22phox) and cytosolic subunits (p67phox and p47phox). Rotenone-elicited extracellular superoxide release in p47phox-deficient macrophages suggested that Rotenone enabled activation of PHOX through a p47phox-independent mechanism. Increased membrane translocation of p67phox, elevated binding of p67phox to Rotenone-treated membrane fractions, and coimmunoprecipitation of p67phox and gp91phox in Rotenone-treated wild-type and p47phox-deficient macrophages indicated that p67phox played a critical role in Rotenone-induced PHOX activation via its direct interaction with gp91phox. Rac1, a Rho-like small GTPase, enhanced p67phox–gp91phox interaction; Rac1 inhibition decreased Rotenone-elicited superoxide release. In conclusion, Rotenone directly interacted with gp91phox; such an interaction triggered membrane translocation of p67phox, leading to PHOX activation and superoxide production.
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critical role for microglial nadph oxidase in Rotenone induced degeneration of dopaminergic neurons
The Journal of Neuroscience, 2003Co-Authors: Huiming Gao, Bin Liu, Jaushyong HongAbstract:Increasing evidence has suggested an important role for environmental toxins such as pesticides in the pathogenesis of Parkinson's disease (PD). Chronic exposure to Rotenone, a common herbicide, reproduces features of Parkinsonism in rats. Mechanistically, Rotenone-induced dopaminergic neurodegeneration has been associated with both its inhibition of neuronal mitochondrial complex I and the enhancement of activated microglia. Our previous studies with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, suggested that NADPH oxidase-derived superoxide might be a major factor in mediating the microglia-enhanced Rotenone neurotoxicity. However, because of the relatively low specificity of these inhibitors, the exact source of superoxide induced by Rotenone remains to be further determined. In this study, using primary mesencephalic cultures from NADPH oxidase—null (gp91phox-/-) or wild-type (gp91phox+/+) mice, we demonstrated a critical role for microglial NADPH oxidase in mediating microglia-enhanced Rotenone neurotoxicity. In neuron—glia cultures, dopaminergic neurons from gp91phox-/- mice were more resistant to Rotenone neurotoxicity than those from gp91phox+/+ mice. However, in neuron-enriched cultures, the neurotoxicity of Rotenone was not different between the two types of mice. More importantly, the addition of microglia prepared from gp91phox+/+ mice but not from gp91phox-/- mice to neuron-enriched cultures markedly increased Rotenone-induced degeneration of dopaminergic neurons. Furthermore, apocynin attenuated Rotenone neurotoxicity only in the presence of microglia from gp91phox+/+ mice. These results indicated that the greatly enhanced neurotoxicity of Rotenone was attributed to the release of NADPH oxidase-derived superoxide from activated microglia. This study also suggested that microglial NADPH oxidase may be a promising target for PD treatment.
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Distinct Role for Microglia in Rotenone-Induced Degeneration of Dopaminergic Neurons
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002Co-Authors: Huiming Gao, Jaushyong Hong, Wanqin Zhang, Bin LiuAbstract:Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in the pathogenesis of Parkinson's disease. In experimental animals the exposure to a common herbicide, Rotenone, induces features of parkinsonism; mechanistically, Rotenone-induced destruction of dopaminergic neurons has been attributed to its inhibition of the activity of neuronal mitochondrial complex I. However, the role of microglia, the resident brain immune cells in Rotenone-induced neurodegeneration, has not been reported. Using primary neuron-enriched and neuron/glia cultures from the rat mesencephalon, we discovered an extraordinary feature for Rotenone-induced degeneration of cultured dopaminergic neurons. Although little neurotoxicity was detected in neuron-enriched cultures after treatment for 8 d with up to 20 nm Rotenone, significant and selective dopaminergic neurodegeneration was observed in neuron/glia cultures 2 d after treatment with 20 nm Rotenone or 8 d after treatment with 1 nm Rotenone. The greatly enhanced neurodegenerative ability of Rotenone was attributed to the presence of glia, especially microglia, because the addition of microglia to neuron-enriched cultures markedly increased their susceptibility to Rotenone. Mechanistically, Rotenone stimulated the release of superoxide from microglia that was attenuated by inhibitors of NADPH oxidase. Furthermore, inhibition of NADPH oxidase or scavenging of superoxide significantly reduced the Rotenone-induced neurotoxicity. This is the first report demonstrating that microglia play a pivotal role in Rotenone-induced degeneration of dopaminergic neurons. The results of this study should advance our understanding of the mechanism of action for pesticides in the pathogenesis of Parkinson's disease.
