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Neuroprotectors in increasing oxime efficacy in the nerve agents poisoning
S186
Abstracts / Toxicology Letters 205S (2011) S180–S300
atures by telemetry, blood oxybate concentrations by GC/MS and blood gases by Bayer Rapidlab 248. Statistics were performed using GraphPad Prism software. Results of the study: Animals in the control and 100 mg kg−1 groups were asymptomatic; greater doses induced coma but all animals woke up suddenly before the completion of the study. The rats receiving 600–1600 mg kg−1 presented a triphasic time-course of temperature evolution and showed significant differences in all parameters except for the minute volume. During the first three hours, total time, inspiratory time, expiratory time and tidal volume increased, respiratory rate decreased. The effect–dose curves allowed calculating the ED50, for each modified parameter, ED-50 was about 600–700 mg kg−1 . These data confirmed a modification of the respiratory parameters, but the study of the toxicokinetic–toxycodynamic relationship showed, that, for greater doses, these effects were not correlated to the blood oxybate concentration. The respiratory modifications stopped when the blood oxybate concentrations were still high, and when the blood pH and bicarbonates concentrations began to increase. doi:10.1016/j.toxlet.2011.05.644
P2021 Neuroprotectors in increasing oxime efficacy in the nerve agents poisoning C.A. Secara Toxicology, Army Center of Medical Researce, Bucharest, Romania
P2022 Oxidative stress in a model of toxic demyelination in rat brain: The effect of piracetam and vinpocetine A.A. Sleem 1,∗ , O.M.E. Abdel-Salam 1 , Y. Ashry 2 , N.A. Salem 3 1
Pharmacology, National Research Centre, Cairo, Egypt, 2 Physiology, National Research Centre, Cairo, Egypt, 3 Pathology, National Research Centre, Cairo, Egypt Purpose: To study the role of oxidative stress and the effect vinpocetine and piracetam in acute demyelination of the rat brain following injection of the DNA chelating agent ethidium bromide. Methods: Starting on the 2nd day of intracerebral injection of ethidium bromide (10 l of 0.1%), different groups of rats were treated with vinpocetine (1.5, 3 or 6 mg/kg), piracetam (150 or 300 mg/kg), or saline (control) orally once a day and for 6 days thereafter. Malondialdehyde, total antioxidant capacity, reduced glutathione, glucose and acetylcholine esteraseactivity were determined in cortex, hippocampus and striatum. Results: Oxidative stress increased in acute demyelination due to ethidium bromide injection into the brain and point to an antioxidant effect and increased glucose availability for vinpocetine. In contrast, piracetam displayed no antioxidant effect in this model and rather increased oxidative stress. Vinpocetine and piracetam displayed variable effects on regional AChE activity, a mechanism which perhaps explains their memory enhancing properties. In the striatum, the highest dose of piracetam counteracted the effect of ethidium bromide. doi:10.1016/j.toxlet.2011.05.646
Object: To select an oxime, with sufficient efficacy to decrease the acute toxicity of soman; to increase the oxime selected efficacy by using galantamine, a centrally acting cholinesterase inhibitor and nicotinic ligand, which can cross the blood brain barrier. Methods: The soman DL50 value experimentally established in the study: 80 g/kg/s.c. The following soman doses were administered to the poisoned and treated study groups: 240 g/kg/s.c; 280 g/kg/s.c and 300 g/kg/s.c. Four Wistar rats study groups were used. The above formula, i.m. administered, 1 min after poisoning, was associated with galantamine (8 mg/kg p.o—30 min prior the poisoning), and experimentally tested. The following antidote formula was used as reference: pyridostigmine (8,1 mg/kg p.o.—30 min prior the poisoning), and ATOX-HI6. The protective ratio and hystopathological analyses were the screening parameters used in the study, in order to show the proposed objectives. Results: The protective ratio of the ATOX-HI6 formula without pretreatment was 3. The protective index of the reference formula was 3.5. The protective index of the experimentally tested antidote formula containing galantamine and ATOX-HI6, was 3.75. Soman induced neurodegeneration in the hippocampus, pyriform cortex and amygdale, were not detected 72 h after soman poisoning, when galantamine is used. The sceisures level was decreased. Conclusions: The AChE inhibitor and neuroprotector compound galantamine administered as pre-treatment, increase, more than pyridostigmine, the atropine—oxime efficacy by increasing the protective ratio, and decreasing soman neurotoxicity. Thus galantamine as pre-treatment emerges as superior antidote therapy against the soman toxicity. doi:10.1016/j.toxlet.2011.05.645
P2023 Central nervous system toxicity of 1-bromopropane: An oxidative stress hypothesis K. Subramanian 1,∗ , Z. Huang 1 , L. Zhang 1 , S. Ichihara 2 , G. Ichihara 1 1 2
Graduate School of Medicine, Nagoya University, Nagoya, Japan, Mie University School of Regional Innovation Studies, Tsu, Japan
Purpose: 1-Bromopropane (1-BP), an alternative solvent for chloroflurocarbons, exhibits neuro-and reproductive toxicities in both animals and humans. However, the mechanism of the toxicity remains elusive. The present study investigated whether 1-bromopropane exposure induces microglial activation in the cerebellum in rats as well as investigating possible role of oxidative stress in the central nervous system toxicity of 1-BP. Methods: Forty-eight male Wistar-ST rats were divided into four groups of 12 rats in each group and were exposed to 1-BP at 0, 400, 800 and 1000 ppm for 8 h/day; 7 days/week for 4 weeks. At the end of the experiment, nine rats were decapitated. The cerebellum and blood were collected for biochemical analysis. Three rats per group were used for immunohistopathological examination. The levels of protein carbonyl, thiobarbituric acid reactive substances (TBARS), beta-amyloid, thrombin, reactive oxygen species (ROS) and nitric oxide were measured in the cerebellum homogenate. Three rats from each group were perfused using 4% paraformaldehyde for immunohistochemistry of cd11b (OX-42). Results: 1-BP induced oxidative stress was evident from a dose-dependent increase in protein carbonyl, TBARS in the cerebellum. We also observed the increase in beta-amyloid, thrombin, ROS and nitric oxide levels dose-dependently. Immunofluorescence staining of OX-42 showed microglial activation in the cerebellum at 1000 ppm. This study showed that exposure to 1-bromopropane induces microglial
Abstracts / Toxicology Letters 205S (2011) S180–S300
atures by telemetry, blood oxybate concentrations by GC/MS and blood gases by Bayer Rapidlab 248. Statistics were performed using GraphPad Prism software. Results of the study: Animals in the control and 100 mg kg−1 groups were asymptomatic; greater doses induced coma but all animals woke up suddenly before the completion of the study. The rats receiving 600–1600 mg kg−1 presented a triphasic time-course of temperature evolution and showed significant differences in all parameters except for the minute volume. During the first three hours, total time, inspiratory time, expiratory time and tidal volume increased, respiratory rate decreased. The effect–dose curves allowed calculating the ED50, for each modified parameter, ED-50 was about 600–700 mg kg−1 . These data confirmed a modification of the respiratory parameters, but the study of the toxicokinetic–toxycodynamic relationship showed, that, for greater doses, these effects were not correlated to the blood oxybate concentration. The respiratory modifications stopped when the blood oxybate concentrations were still high, and when the blood pH and bicarbonates concentrations began to increase. doi:10.1016/j.toxlet.2011.05.644
P2021 Neuroprotectors in increasing oxime efficacy in the nerve agents poisoning C.A. Secara Toxicology, Army Center of Medical Researce, Bucharest, Romania
P2022 Oxidative stress in a model of toxic demyelination in rat brain: The effect of piracetam and vinpocetine A.A. Sleem 1,∗ , O.M.E. Abdel-Salam 1 , Y. Ashry 2 , N.A. Salem 3 1
Pharmacology, National Research Centre, Cairo, Egypt, 2 Physiology, National Research Centre, Cairo, Egypt, 3 Pathology, National Research Centre, Cairo, Egypt Purpose: To study the role of oxidative stress and the effect vinpocetine and piracetam in acute demyelination of the rat brain following injection of the DNA chelating agent ethidium bromide. Methods: Starting on the 2nd day of intracerebral injection of ethidium bromide (10 l of 0.1%), different groups of rats were treated with vinpocetine (1.5, 3 or 6 mg/kg), piracetam (150 or 300 mg/kg), or saline (control) orally once a day and for 6 days thereafter. Malondialdehyde, total antioxidant capacity, reduced glutathione, glucose and acetylcholine esteraseactivity were determined in cortex, hippocampus and striatum. Results: Oxidative stress increased in acute demyelination due to ethidium bromide injection into the brain and point to an antioxidant effect and increased glucose availability for vinpocetine. In contrast, piracetam displayed no antioxidant effect in this model and rather increased oxidative stress. Vinpocetine and piracetam displayed variable effects on regional AChE activity, a mechanism which perhaps explains their memory enhancing properties. In the striatum, the highest dose of piracetam counteracted the effect of ethidium bromide. doi:10.1016/j.toxlet.2011.05.646
Object: To select an oxime, with sufficient efficacy to decrease the acute toxicity of soman; to increase the oxime selected efficacy by using galantamine, a centrally acting cholinesterase inhibitor and nicotinic ligand, which can cross the blood brain barrier. Methods: The soman DL50 value experimentally established in the study: 80 g/kg/s.c. The following soman doses were administered to the poisoned and treated study groups: 240 g/kg/s.c; 280 g/kg/s.c and 300 g/kg/s.c. Four Wistar rats study groups were used. The above formula, i.m. administered, 1 min after poisoning, was associated with galantamine (8 mg/kg p.o—30 min prior the poisoning), and experimentally tested. The following antidote formula was used as reference: pyridostigmine (8,1 mg/kg p.o.—30 min prior the poisoning), and ATOX-HI6. The protective ratio and hystopathological analyses were the screening parameters used in the study, in order to show the proposed objectives. Results: The protective ratio of the ATOX-HI6 formula without pretreatment was 3. The protective index of the reference formula was 3.5. The protective index of the experimentally tested antidote formula containing galantamine and ATOX-HI6, was 3.75. Soman induced neurodegeneration in the hippocampus, pyriform cortex and amygdale, were not detected 72 h after soman poisoning, when galantamine is used. The sceisures level was decreased. Conclusions: The AChE inhibitor and neuroprotector compound galantamine administered as pre-treatment, increase, more than pyridostigmine, the atropine—oxime efficacy by increasing the protective ratio, and decreasing soman neurotoxicity. Thus galantamine as pre-treatment emerges as superior antidote therapy against the soman toxicity. doi:10.1016/j.toxlet.2011.05.645
P2023 Central nervous system toxicity of 1-bromopropane: An oxidative stress hypothesis K. Subramanian 1,∗ , Z. Huang 1 , L. Zhang 1 , S. Ichihara 2 , G. Ichihara 1 1 2
Graduate School of Medicine, Nagoya University, Nagoya, Japan, Mie University School of Regional Innovation Studies, Tsu, Japan
Purpose: 1-Bromopropane (1-BP), an alternative solvent for chloroflurocarbons, exhibits neuro-and reproductive toxicities in both animals and humans. However, the mechanism of the toxicity remains elusive. The present study investigated whether 1-bromopropane exposure induces microglial activation in the cerebellum in rats as well as investigating possible role of oxidative stress in the central nervous system toxicity of 1-BP. Methods: Forty-eight male Wistar-ST rats were divided into four groups of 12 rats in each group and were exposed to 1-BP at 0, 400, 800 and 1000 ppm for 8 h/day; 7 days/week for 4 weeks. At the end of the experiment, nine rats were decapitated. The cerebellum and blood were collected for biochemical analysis. Three rats per group were used for immunohistopathological examination. The levels of protein carbonyl, thiobarbituric acid reactive substances (TBARS), beta-amyloid, thrombin, reactive oxygen species (ROS) and nitric oxide were measured in the cerebellum homogenate. Three rats from each group were perfused using 4% paraformaldehyde for immunohistochemistry of cd11b (OX-42). Results: 1-BP induced oxidative stress was evident from a dose-dependent increase in protein carbonyl, TBARS in the cerebellum. We also observed the increase in beta-amyloid, thrombin, ROS and nitric oxide levels dose-dependently. Immunofluorescence staining of OX-42 showed microglial activation in the cerebellum at 1000 ppm. This study showed that exposure to 1-bromopropane induces microglial