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Zhe-shan Quan - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the anticonvulsant activity of 6 4 chlorophenyoxy tetrazolo 5 1 a phthalazine in various experimental seizure models in mice
Pharmacological Reports, 2010Co-Authors: Xianqing Deng, Zhe-shan QuanAbstract:Abstract This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The Neurotoxicity of QUAN-0808 was investigated using the rotarod Neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED 50 = 6.8 mg/ kg) and lower Neurotoxicity (median toxic dose, TD 50 = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED 50 = 24 mg/kg) against MES-induced seizure with low Neurotoxicity (TD 50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.
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Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice
Pharmacological reports : PR, 2010Co-Authors: Xian-yu Sun, Xianqing Deng, Cheng-xi Wei, Zhi-gang Sun, Zhe-shan QuanAbstract:Abstract This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The Neurotoxicity of QUAN-0808 was investigated using the rotarod Neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED 50 = 6.8 mg/ kg) and lower Neurotoxicity (median toxic dose, TD 50 = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED 50 = 24 mg/kg) against MES-induced seizure with low Neurotoxicity (TD 50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.
Zhizhong Pan - One of the best experts on this subject based on the ideXlab platform.
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neuroprotective effect of neurotropin on chronic oxaliplatin induced Neurotoxicity in stage i and stage ii colorectal cancer patients results from a prospective randomised single centre pilot clinical trial
Annals of Oncology, 2012Co-Authors: Rongxin Zhang, Gang Chen, D S Wan, Zhizhong PanAbstract:ABSTRACT Background Oxaliplatin is effective in adjuvant and first-line colorectal cancer chemotherapy. Oxaliplatin-induced severe chronic Neurotoxicity is the main dose-limiting adverse event. No standard treatment for oxaliplatin-induced chronic Neurotoxicity has been identified. Materials and methods We conducted a prospective pilot clinical trial to explore whether neurotropin has neuroprotective effects on chronic Neurotoxicity. From May 1 2010 to July 1 2011, 80 stage II and III colorectal cancer patients who were eligible to receive oxaliplatin-based chemotherapy voluntarily enrolled in the trial. The patients were randomly divided into 2 groups, one of which received neurotropin treatment. Results The patients in the control group experienced significantly ≥ grade 2 and ≥ grade 3 Neurotoxicity (by NCI CTCAE grading) than did those in the neurotropin group (60.9% vs. 38%, for at least grade 2 Neurotoxicity, P = 0.001; 39% vs. 2.7%, for at least grade 3 Neurotoxicity, P Treatment related AES Toxicity Neurotropin group Control group P value Peripheral neuropathy (NCI CTCAE version 4.0 ) ≥ grade 1 38 (100%) 41 (100%) — ≥ grade 2 8 (21.1%) 25 (60.9%) 0.001a ≥ grade 3 1 (2.7%) 16 (39%) Neurotoxicity (Oxaliplatin-Specific Neurotoxicity grading) ≥ grade 1 38 (100%) 41 (100%) —- ≥ grade 2 5 (12.5%) 21 (51.2%) 0.001b ≥ grade 3 0 (0%) 4 (9.8%) 0.117c Hand-foot syndrome ≥grade 1 28 (73.7%) 23 (56.1%) 0.103a ≥grade 2 5 (13.2%) 3 (7.3%) 0.627b ≥grade 3 1 (2.6%) 0 (0%) 0.481c White blood cell count decreased ≥grade 1 17 (44.7%) 15 (36.6%) 0.461a ≥grade 2 2 (5.3%) 4(9.8%) 0.958b Thrombocytopenia ≥grade 1 3 (7.9%) 8 (19.5%) 0.244b Diarrhea ≥grade 1 7 (18.4%) 9 (22%) 0.696a Neutrophil count decreased ≥grade 1 14 (36.8%) 16 (39%) 0.842a ≥grade 2 3 (7.9%) 6 (14.6%) 0.557b Hepatobiliary disorders ≥grade 1 8 (21.1%) 9 (22%) 0.923a Renal disorder ≥grade 1 1 (2.6%) 2 (4.9%) 1.0c Nausea ≥grade 1 25 (65.8%) 21 (51.2%) 0.190a Vomiting ≥grade 1 6 (15.8%) 8 (19.5%) 0.665b aχ2test b Continuity correction c Fisher's exact test Conclusion Neurotropin combined with oxaliplatin decreases chronic Neurotoxicity effectively and safely. Disclosure All authors have declared no conflicts of interest.
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neuroprotective effect of neurotropin on chronic oxaliplatin induced Neurotoxicity in stage ii and stage iii colorectal cancer patients results from a prospective randomised single centre pilot clinical trial
International Journal of Colorectal Disease, 2012Co-Authors: Rongxin Zhang, D S Wan, Zhizhong Pan, Peirong Ding, Ling Heng Kong, Gang ChenAbstract:Background Oxaliplatin is effective in adjuvant and first-line colorectal cancer chemotherapy. Oxaliplatin-induced severe chronic Neurotoxicity is the main dose-limiting adverse event. No standard treatment for oxaliplatin-induced chronic Neurotoxicity has been identified.
Matthew C. Kiernan - One of the best experts on this subject based on the ideXlab platform.
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paclitaxel induced neuropathy potential association of mapt and gsk3b genotypes
BMC Cancer, 2014Co-Authors: Cindy S.-y. Lin, Arun V. Krishnan, Susanna B. Park, Michael Friedlander, John B J Kwok, Clement T Loy, Craig R Lewis, Matthew C. KiernanAbstract:Paclitaxel treatment produces dose-limiting peripheral Neurotoxicity, which adversely affects treatment and long-term outcomes. In the present study, the contribution of genetic polymorphisms to paclitaxel-induced Neurotoxicity were assessed in 21 patients, focusing on polymorphisms involved in the tau-microtubule pathway, an important target of paclitaxel involved in Neurotoxicity development. Polymorphisms in the microtubule-associated protein tau (MAPT) gene (haplotype 1 and rs242557 polymorphism) and the glycogen synthase kinase-3β (GSK3β) gene (rs6438552 polymorphism) were investigated. Neurotoxicity was assessed using neuropathy grading scales, neurophysiological studies and patient questionnaires. A significant relationship between the GSK-3B rs6438552 polymorphism and paclitaxel-induced Neurotoxicity was evident. Polymorphisms in tau-associated genes may contribute to the development of paclitaxel-induced Neurotoxicity, although larger series will be necessary to confirm these findings.
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oxaliplatin induced Neurotoxicity changes in axonal excitability precede development of neuropathy
Brain, 2009Co-Authors: Susanna B. Park, Cindy S.-y. Lin, Arun V. Krishnan, David Goldstein, Michael Friedlander, Matthew C. KiernanAbstract:Administration of oxaliplatin, a platinum-based chemotherapy used extensively in the treatment of colorectal cancer, is complicated by prominent dose-limiting Neurotoxicity. Acute Neurotoxicity develops following oxaliplatin infusion and resolves within days, while chronic neuropathy develops progressively with higher cumulative doses. To investigate the pathophysiology of oxaliplatin-induced Neurotoxicity and neuropathy, clinical grading scales, nerve conduction studies and a total of 905 axonal excitability studies were undertaken in a cohort of 58 consecutive oxaliplatin-treated patients. Acutely following individual oxaliplatin infusions, significant changes were evident in both sensory and motor axons in recovery cycle parameters (P 0.05), consistent with the purely sensory symptoms of chronic oxaliplatin-induced neuropathy. Sensory abnormalities occurred prior to significant reduction in compound sensory amplitude and the development of neuropathy (P < 0.01). Sensory excitability abnormalities that developed during early treatment cycles (cumulative dose 294 +/- 16 mg/m(2) oxaliplatin; P < 0.05) were able to predict final clinical outcome on an individual patient basis in 80% of patients. As such, sensory axonal excitability techniques may provide a means to identify pre-clinical oxaliplatin-induced nerve dysfunction prior to the onset of chronic neuropathy. Furthermore, patients with severe Neurotoxicity at treatment completion demonstrated greater excitability changes (P < 0.05) than those left with mild or moderate Neurotoxicity, suggesting that assessment of sensory excitability parameters may provide a sensitive biomarker of severity for oxaliplatin-induced Neurotoxicity.
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acute abnormalities of sensory nerve function associated with oxaliplatin induced Neurotoxicity
Journal of Clinical Oncology, 2009Co-Authors: Susanna B. Park, Cindy S.-y. Lin, Arun V. Krishnan, David Goldstein, Michael Friedlander, Matthew C. KiernanAbstract:Purpose Neurotoxicity is becoming increasingly recognized as the major dose-limiting toxicity of oxaliplatin. Because the mechanism of oxaliplatin-induced Neurotoxicity remains unclear, the present study investigated the potential of axonal excitability techniques in identifying pathophysiologic mechanisms and early markers of nerve dysfunction. Patients and Methods Measures of sensory axonal excitability were recorded before and after infusion over 88 treatment cycles in 25 patients with colorectal cancer, who received a total oxaliplatin dose of 766 ± 56 mg/m2. Neurologic assessment, clinical rating scales, and routine nerve conduction studies were performed. Results By completion of treatment, 16% of patients had developed severe (grade 3) Neurotoxicity, and oxaliplatin dose reduction or cessation as a result of Neurotoxicity was required in 40% of patients. Changes in axonal excitability occurred after infusion and could be explained on the basis of alterations in axonal membrane sodium (Na+) channel ...
Xianqing Deng - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the anticonvulsant activity of 6 4 chlorophenyoxy tetrazolo 5 1 a phthalazine in various experimental seizure models in mice
Pharmacological Reports, 2010Co-Authors: Xianqing Deng, Zhe-shan QuanAbstract:Abstract This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The Neurotoxicity of QUAN-0808 was investigated using the rotarod Neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED 50 = 6.8 mg/ kg) and lower Neurotoxicity (median toxic dose, TD 50 = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED 50 = 24 mg/kg) against MES-induced seizure with low Neurotoxicity (TD 50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.
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Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice
Pharmacological reports : PR, 2010Co-Authors: Xian-yu Sun, Xianqing Deng, Cheng-xi Wei, Zhi-gang Sun, Zhe-shan QuanAbstract:Abstract This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The Neurotoxicity of QUAN-0808 was investigated using the rotarod Neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED 50 = 6.8 mg/ kg) and lower Neurotoxicity (median toxic dose, TD 50 = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED 50 = 24 mg/kg) against MES-induced seizure with low Neurotoxicity (TD 50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.
Jaushyong Hong - One of the best experts on this subject based on the ideXlab platform.
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nadph oxidase mediates lipopolysaccharide induced Neurotoxicity and proinflammatory gene expression in activated microglia
Journal of Biological Chemistry, 2004Co-Authors: Tongguang Wang, Belinda Wilson, Michelle L Block, Jaushyong HongAbstract:Abstract Parkinson's disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. We have previously reported that lipopolysaccharide (LPS)-induced degeneration of dopaminergic neurons is mediated by the release of proinflammatory factors from activated microglia. Here, we report the pivotal role of NADPH oxidase in inflammation-mediated Neurotoxicity, where the LPS-induced loss of nigral dopaminergic neurons in vivo was significantly less pronounced in NADPH oxidase-deficient (PHOX-/-) mice when compared with control (PHOX+/+) mice. Dopaminergic neurons in primary mensencephalic neuron-glia cultures from PHOX+/+ mice were significantly more sensitive to LPS-induced Neurotoxicity in vitro when compared with PHOX-/- mice. Further, PHOX+/+ neuron-glia cultures chemically depleted of microglia failed to show dopaminergic Neurotoxicity with the addition of LPS. Neuron-enriched cultures from both PHOX+/+ mice and PHOX-/- mice also failed to show any direct LPS-induced dopaminergic Neurotoxicity. However, the addition of PHOX+/+ microglia to neuron-enriched cultures from either strain resulted in reinstatement of LPS-induced dopaminergic Neurotoxicity, supporting the role of microglia as the primary source of NADPH oxidase-generated insult and Neurotoxicity. Immunostaining for F4/80 in mensencephalic neuron-glia cultures revealed that PHOX-/- microglia failed to show activated morphology at 10 h, suggesting an important role of reactive oxygen species (ROS) generated from NADPH oxidase in the early activation of microglia. LPS also failed to elicit extracellular superoxide and produced low levels of intracellular ROS in microglia-enriched cultures from PHOX-/- mice. Gene expression and release of tumor necrosis factor α was much lower in PHOX-/- mice than in control PHOX+/+ mice. Together, these results demonstrate the dual neurotoxic functions of microglial NADPH oxidase: 1) the production of extracellular ROS that is toxic to dopamine neurons and 2) the amplification of proinflammatory gene expression and associated Neurotoxicity.
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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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microglia enhance β amyloid peptide induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species
Journal of Neurochemistry, 2002Co-Authors: Liya Qin, Bin Liu, Yuxin Liu, Cynthia L Cooper, Belinda Wilson, Jaushyong HongAbstract:The purpose of this study was to assess and compare the toxicity of β-amyloid (Aβ) on primary cortical and mesencephalic neurons cultured with and without microglia in order to determine the mechanism underlying microglia-mediated Aβ-induced Neurotoxicity. Incubation of cortical or mesencephalic neuron-enriched and mixed neuron–glia cultures with Aβ(1–42) over the concentration range 0.1–6.0 μm caused concentration-dependent Neurotoxicity. High concentrations of Aβ (6.0 μm for cortex and 1.5–2.0 μm for mesencephalon) directly injured neurons in neuron-enriched cultures. In contrast, lower concentrations of Aβ (1.0–3.0 μm for cortex and 0.25–1.0 μm for mesencephalon) caused significant Neurotoxicity in mixed neuron–glia cultures, but not in neuron- enriched cultures. Several lines of evidence indicated that microglia mediated the potentiated Neurotoxicity of Aβ, including the observations that low concentrations of Aβ activated microglia morphologically in neuron–glia cultures and that addition of microglia to cortical neuron–glia cultures enhanced Aβ-induced Neurotoxicity. To search for the mechanism underlying the microglia-mediated effects, several proinflammatory factors were examined in neuron–glia cultures. Low doses of Aβ significantly increased the production of superoxide anions, but not of tumor necrosis factor-α, interleukin-1β or nitric oxide. Catalase and superoxide dismutase significantly protected neurons from Aβ toxicity in the presence of microglia. Inhibition of NADPH oxidase activity by diphenyleneiodonium also prevented Aβ-induced Neurotoxicity in neuron–glia mixed cultures. The role of NADPH oxidase-generated superoxide in mediating Aβ-induced Neurotoxicity was further substantiated by a study which showed that Aβ caused less of a decrease in dopamine uptake in mesencephalic neuron–glia cultures from NADPH oxidase-deficient mutant mice than in that from wild-type controls. This study demonstrates that one of the mechanisms by which microglia can enhance the Neurotoxicity of Aβ is via the production of reactive oxygen species.
