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Jane C.F. Chang Paul Ciaccio Patricia Schroeder Lindsay Wright Russell Westwood Anna-Lena Berg 《Journal of toxicologic pathology》2014,27(1):31-42
AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine
(5-HT1B) receptor, was explored as a potential treatment for depression. To
support clinical trials, repeat dose toxicity studies in rats and dogs were conducted.
Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month
study, there were minimal neuronal vacuolation in the brain, a marked increase in liver
enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD),
and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month
study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86
days. Extensive pathologic changes were seen in all animals in retina epithelium
(inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber
degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic
and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung,
kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues.
Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and
pathology study showed that the concentration of AZD3783 in the brain was approximately 4
times higher than in the plasma after 4 weeks of dosing, however, they were similar in all
regions examined, and did not correlate with areas with pathologic findings. Our findings
with AZD3783 in dogs have not been reported previously with other CNS compounds that
effect through serotonergic pharmacology. 相似文献
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The effect of tri-o-cresyl phosphate (TOCP) and methamidophos (MET) on potassium-stimulated 45Ca uptake by brain synaptosomes in hens was studied. An in vivo test showed that TOCP increased potassium-stimulated calcium uptake 2 h after its administration, but that verapamil suppressed the enhancement of this calcium uptake. An in vitro test showed that lower concentrations of TOCP stimulated calcium uptake by synaptosomes, but that higher concentrations inhibited the uptake. In contrast, all tested concentrations of MET obviously inhibited calcium uptake; however, since calcium uptake was decreased by the administration of verapamil plus either TOCP or MET, the mechanism by which TOCP affects the voltage-operated calcium channel may be different from that of MET. The disruption of calcium homeostasis may be involved in organophosphate-induced delayed neurotoxicity (OPIDN). Calcium channel blocker may ameliorate OPIDN by maintaining calcium homeostasis in nerve cells. 相似文献
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为了测定瑞香狼毒超临界CO2萃取物对朱砂叶螨的触杀毒力,并了解其作用机理,笔者采用玻片浸渍法测定瑞香狼毒超临界CO2萃取物(SCE)对朱砂叶螨的触杀毒力,观察其对朱砂叶螨的致毒症状;结果表明:SCE对朱砂叶螨24 h的触杀LC50值为2.411 mg/mL;中毒试螨表现出类似神经毒剂的致毒症状,如兴奋、痉挛等。随后测定了SCE对朱砂叶螨神经系统靶标酶(乙酰胆碱酯酶、单胺氧化酶、Na+-K+-ATP酶和Ca2+-Mg2+-ATP酶)活性的影响。结果表明,SCE能够显著抑制试螨乙酰胆碱酯酶、单胺氧化酶、Na+-K+-ATP酶和Ca2+-Mg2+-ATP酶的活性;据此推测,SCE对朱砂叶螨可能具有神经毒性。 相似文献
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Yoot Mo Lee Min Jae Seong Jae Woong Lee Yong Kyung Lee Tae Myoung Kim Sang-Yoon Nam Dae Joong Kim Young Won Yun Tae Seong Kim Soon Young Han Jin Tae Hong 《Journal of veterinary science (Suw?n-si, Korea)》2007,8(1):27-38
Bisphenol A (BPA), a ubiquitous environmental contaminant, has been shown to cause developmental toxicity and carcinogenic effects. BPA may have physiological activity through estrogen receptor (ER) -α and -β, which are expressed in the central nervous system. We previously found that exposure of BPA to immature mice resulted in behavioral alternation, suggesting that overexposure of BPA could be neurotoxic. In this study, we further investigated the molecular neurotoxic mechanisms of BPA. BPA increased vulnerability (decrease of cell viability and differentiation, and increase of apoptotic cell death) of undifferentiated PC12 cells and cortical neuronal cells isolated from gestation 18 day rat embryos in a concentration-dependent manner (more than 50 µM). The ER antagonists, ICI 182,780, and tamoxifen, did not block these effects. The cell vulnerability against BPA was not significantly different in the PC12 cells overexpressing ER-α and ER-β compared with PC12 cells expressing vector alone. In addition, there was no difference observed between BPA and 17-β estradiol, a well-known agonist of ER receptor in the induction of neurotoxic responses. Further study of the mechanism showed that BPA significantly activated extracellular signal-regulated kinase (ERK) but inhibited anti-apoptotic nuclear factor kappa B (NF-κB) activation. In addition, ERK-specific inhibitor, PD 98,059, reversed BPA-induced cell death and restored NF-κB activity. This study demonstrated that exposure to BPA can cause neuronal cell death which may eventually be related with behavioral alternation in vivo. However, this neurotoxic effect may not be directly mediated through an ER receptor, as an ERK/NF-κB pathway may be more closely involved in BPA-induced neuronal toxicity. 相似文献
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Controversies surrounding the safety of N,N‐diethyl‐meta‐toluamide (DEET) when used as an insect repellent are centered around conflicting findings in the scientific literature and inaccurate reporting in the public media. Lethal cases of DEET poisoning are few, and usually due to deliberate or other overdoses that ignore product label instructions. Deleterious effects of DEET typically involve skin reactions and even when encephalopathies, such as seizures, occur they often abate without sequelae. Recent mode‐of‐action studies prove it has little direct effect on acetylcholinesterase, and have identified G protein‐coupled receptors as a site of action deserving of further investigation. Studies with pregnant women found that DEET had no effect on the developing fetus from proper use and its continued deployment as a repellent is endorsed by both the Centers for Disease Control and Prevention and the Environmental Protection Agency, with specific recommendations of how it should be used on children. © 2019 Society of Chemical Industry 相似文献