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Neurotoxicity
Kinds of Neurotoxicity Selected AbstractsNERVE GROWTH FACTOR RESCUE OF CISPLATIN NEUROTOXICITY IS MEDIATED THROUGH THE HIGH AFFINITY RECEPTOR: STUDIES IN PC12 CELLS AND P75 NULL MOUSE DORSAL ROOT GANGLIAJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2002SJ Fischer Nerve growth factor (NGF) rescues dorsal root ganglion neurons and PC12 cells from cisplatin-induced cell death. Two model systems were used to demonstrate that rescue is mediated through the high affinity NGF receptor. In dorsal root ganglion (DRG) neurons isolated from p75(,/,) and control mice, 20 ng/ml NGF completely prevented cisplatin-induced death. In PC12 cells, we overexpressed receptor chimeras between the tumor necrosis factor and NGF receptors. We demonstrated that activation of the intracellular domain of Trk A is responsible for the NGF rescue effect. [source] Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: how strong is the evidence for persistent brain damage?ADDICTION, Issue 3 2006E. Gouzoulis-Mayfrank ABSTRACT Background The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine: MDMA and some analogues) causes selective and persistent neurotoxic damage of central serotonergic neurones in laboratory animals. Serotonin plays a role in numerous functional systems in the central nervous system (CNS). Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine and cognitive disorders could be expected in humans following MDMA-induced neurotoxic brain damage. Aims In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies with drug users. The aim of this paper was to review this literature and weigh the strength of the evidence for persistent brain damage in ecstasy users. Methods We used Medline to view all available publications on ,ecstasy' or ,MDMA'. All available studies dealing with ecstasy users entered this analysis. Findings and conclusions Despite large methodological problems the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial restitution may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive, particularly memory, impairments with heavy ecstasy use. However, the evidence cannot be considered definite and the issues of possible pre-existing traits or the effects of polydrug use are not resolved. Recommendations Questions about the neurotoxic effects of ecstasy on the brain remain highly topical in light of its popularity among young people. More longitudinal and prospective studies are clearly needed in order to obtain a better understanding of the possible long-term sequelae of ecstasy use in humans. [source] Neurotoxicity upon infusion of dimethylsulfoxide-cryopreserved peripheral blood stem cells in patients with and without pre-existing cerebral diseaseEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2007Lutz P. Mueller Abstract Objective:, Toxicity related to the infusion of dimethylsulfoxide (DMSO)-cryopreserved peripheral blood stem cells (DMSO-PBSC) mainly comprises cardiovascular events. Fatal neurotoxicity has been reported in a few cases. DMSO represents the putative causative agent of such rare toxicities and elaborate strategies to replace DMSO would benefit from the identification of predisposing factors for DMSO-related toxicities. Methods:, Here, we report on DMSO-related neurotoxicity in a series of patients (n = 51) receiving DMSO-PBSC. The analyzed patient-series included eight patients with pre-existing cerebral disease, partially with a history of epileptic seizures. Results:, Neurotoxicity was observed in only one patient who suffered from a generalized tonic seizure upon infusion of DMSO-PBSC and for which the clinical course is reported herein. No neurotoxicity was observed in the group of patients with pre-existing neurological disease. Furthermore, no neurotoxicity was observed in patients who received particularly large volumes of DMSO. In all patients, mild non-neurological side effects occurred but besides the reported seizure no other severe adverse events were observed upon PBSC-infusion. Conclusions:, To our knowledge, this is the first report addressing the identification of predisposing factors for DMSO-related neurotoxicty. We conclude that infusion of DMSO-PBSC can be performed safely in patients with pre-existing cerebral disease despite the rare occurrence of severe neurotoxicity. Retrospective multicenter studies are warranted to identify patients who would benefit from elaborate methods of DMSO-replacement. [source] Neurotoxicity of acyclovir and valacyclovir in a hemodialyzed patientEUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2004S. Strumia No abstract is available for this article. [source] Neurotoxicity of channel mutations in heterologously expressed ,7-nicotinic acetylcholine receptorsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2001Ronald J. Lukas Abstract Nicotinic acetylcholine receptors (nAChR) composed of chick ,7 subunits mutated to threonine at amino acid valine-251 in the putative channel-lining M2 domain were expressed heterologously in several neuron-like and non-neuronal mammalian cell lines. Expression of mutant ,7-nAChR is toxic to neuron-like cells of the human neuroblastoma cell lines SH-SY5Y and IMR-32, but not to several other cell types. Growth in the presence of the ,7-nAChR antagonist methyllycaconitine (MLA) protects against neurotoxicity, as does gradual downregulation of functional, mutant ,7-nAChR in surviving transfected SH-SY5Y cells. Relative to wild-type ,7-nAChR, functional ,7-nAChR mutants show a higher affinity for agonists, slower rates of desensitization, and sensitivity to dihydro-,-erythroidine (DH,E) as an agonist, but they retain sensitivity to MLA as a competitive antagonist. These findings demonstrate that expression of hyperfunctional, mutant forms of Ca2+ -permeable ,7-nAChR is toxic to neuron-like cells. [source] A ,-amino acid modified heptapeptide containing a designed recognition element disrupts fibrillization of the amyloid ,-peptideJOURNAL OF PEPTIDE SCIENCE, Issue 9 2010Valeria Castelletto Abstract We study the complex formation of a peptide ,A,AKLVFF, previously developed by our group, with A,(1,42) in aqueous solution. Circular dichroism spectroscopy is used to probe the interactions between ,A,AKLVFF and A,(1,42), and to study the secondary structure of the species in solution. Thioflavin T fluorescence spectroscopy shows that the population of fibers is higher in ,A,AKLVFF/A,(1,42) mixtures compared to pure A,(1,42) solutions. TEM and cryo-TEM demonstrate that co-incubation of ,A,AKLVFF with A,(1,42) causes the formation of extended dense networks of branched fibrils, very different from the straight fibrils observed for A,(1,42) alone. Neurotoxicity assays show that although ,A,AKLVFF alters the fibrillization of A,(1,42), it does not decrease the neurotoxicity, which suggests that toxic oligomeric A,(1,42) species are still present in the ,A,AKLVFF/A,(1,42) mixtures. Our results show that our designed peptide binds to A,(1,42) and changes the amyloid fibril morphology. This is shown to not necessarily translate into reduced toxicity. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Effects of the Glucocorticoid Antagonist, Mifepristone, on the Consequences of Withdrawal From Long Term Alcohol ConsumptionALCOHOLISM, Issue 12 2008Catherine Jacquot Background:, Studies were carried out to test the hypothesis that administration of a glucocorticoid Type II receptor antagonist, mifepristone (RU38486), just prior to withdrawal from chronic alcohol treatment, would prevent the consequences of the alcohol consumption and withdrawal in mice. Materials and Methods:, The effects of administration of a single intraperitoneal dose of mifepristone were examined on alcohol withdrawal hyperexcitability. Memory deficits during the abstinence phase were measured using repeat exposure to the elevated plus maze, the object recognition test, and the odor habituation/discrimination test. Neurotoxicity in the hippocampus and prefrontal cortex was examined using NeuN staining. Results:, Mifepristone reduced, though did not prevent, the behavioral hyperexcitability seen in TO strain mice during the acute phase of alcohol withdrawal (4 hours to 8 hours after cessation of alcohol consumption) following chronic alcohol treatment via liquid diet. There were no alterations in anxiety-related behavior in these mice at 1 week into withdrawal, as measured using the elevated plus maze. However, changes in behavior during a second exposure to the elevated plus maze 1 week later were significantly reduced by the administration of mifepristone prior to withdrawal, indicating a reduction in the memory deficits caused by the chronic alcohol treatment and withdrawal. The object recognition test and the odor habituation and discrimination test were then used to measure memory deficits in more detail, at between 1 and 2 weeks after alcohol withdrawal in C57/BL10 strain mice given alcohol chronically via the drinking fluid. A single dose of mifepristone given at the time of alcohol withdrawal significantly reduced the memory deficits in both tests. NeuN staining showed no evidence of neuronal loss in either prefrontal cortex or hippocampus after withdrawal from chronic alcohol treatment. Conclusions:, The results suggest mifepristone may be of value in the treatment of alcoholics to reduce their cognitive deficits. [source] Alcohol-Induced Neurodegeneration: When, Where and Why?ALCOHOLISM, Issue 2 2004Fulton T. Crews Abstract: This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were (1) Characterization of Synaptic Loss in Cerebella of Mature and Senescent Rats after Lengthy Chronic Ethanol Consumption, (2) Ethanol Withdrawal Both Causes Neurotoxicity and Inhibits Neuronal Recovery Processes in Rat Organotypic Hippocampal Cultures, (3) Binge Drinking-Induced Brain Damage: Genetic and Age Related Effects, (4) Binge Ethanol-Induced Brain Damage: Involvement of Edema, Arachidonic Acid and Tissue Necrosis Factor , (TNF,), and (5) Cyclic AMP Cascade, Stem Cells and Ethanol. Taken together these studies suggest that alcoholic neurodegeneration occurs through multiple mechanisms and in multiple brain regions both during intoxication and withdrawal. [source] Polyamines Contribute to Ethanol Withdrawal-Induced Neurotoxicity in Rat Hippocampal Slice Cultures Through Interactions With the NMDA ReceptorALCOHOLISM, Issue 7 2003D. Alex Gibson Background: Several reports demonstrate that withdrawal from long-term ethanol exposure is associated with significant central nervous system neurotoxicity, produced at least in part by increased activity of N -methyl-d-aspartate receptors (NMDARs). Recent evidence suggests that elevations in the synthesis and release of the polyamines spermidine and spermine, which are known modulators of NMDARs, contribute to the increased activity of the receptor during ethanol withdrawal. Therefore, the goal of this investigation was to examine what role, if any, spermidine and spermine have in the generation of ethanol withdrawal-induced neurotoxicity. Methods: Neurotoxicity (measured as fluorescence of the cell death indicator propidium iodide, PI), glutamate release (measured by high-performance liquid chromatography analysis), and polyamine concentrations (by high-performance liquid chromatography) were measured in rat hippocampal slice cultures undergoing withdrawal from chronic (10 day) ethanol exposure (100 mM). In addition, the effects of the polyamine synthesis inhibitor di-fluoro-methyl-ornithine (DFMO, 0.1,100 nM) and NMDAR polyamine-site antagonists ifenprodil, arcaine, and agmatine (1 nM-100 ,M) on ethanol withdrawal- and NMDA-induced neurotoxicity were measured. Results: Ethanol withdrawal significantly increased glutamate release (peaking at 18 hr with a 53% increase), increased concentrations of putrescine and spermidine (136% and 139% increases, respectively, at 18 hr), and produced significant cytotoxicity in the CA1 hippocampal region (56% increase in PI staining relative to controls) of the cultures. The cell death produced by ethanol withdrawal was significantly inhibited by ifenprodil (IC50= 14.9 nM), arcaine (IC50= 37.9 nM), agmatine (IC50= 41.5 nM), and DFMO (IC50= 0.6 nM). NMDA (5 ,M) significantly increased PI staining in the CA1 region of the hippocampal cultures (365% relative to controls), but ifenprodil, arcaine, agmatine, and DFMO all failed to significantly affect this type of toxicity. Conclusions: These data implicate a role for polyamines in ethanol withdrawal-induced neurotoxicity and suggest that inhibiting the actions of polyamines on NMDARs may be neuroprotective under these conditions. [source] Early steroid withdrawal after liver transplantation: The canadian tacrolimus versus microemulsion cyclosporin a trial: 1-year follow-upLIVER TRANSPLANTATION, Issue 6 2003Paul Greig Corticosteroid therapy contributes significant toxicity to liver transplantation. The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A (micro-CsA). The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation. From the seven Canadian adult liver transplant centers, 143 patients were randomly allocated oral treatment with either tacrolimus (n = 71) or micro-CsA (n = 72), together with corticosteroids and azathioprine. Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months, and prednisone ,0.15 mg/kg/d. In eligible patients, the daily steroid dose was reduced by 2.5 mg each month until complete discontinuation was achieved. At 1 year after transplantation, 75% of the tacrolimus patients and 63% of the micro-CsA patients were steroid-free (P = .20). Of all of the patients who became eligible for steroid withdrawal, steroid discontinuation was achieved in over 80%. One-year patient survival was 97% with tacrolimus and 89% with micro-CsA (P = .052). Graft survival was 97% and 86%, respectively (P = .017). The overall incidence of acute rejection during the first year was 35% with tacrolimus and 43% with micro-CsA (P = .26). There was no difference in survival, acute rejection, or rate of steroid withdrawal when adjusting for hepatitis C. All acute rejection episodes experienced during steroid withdrawal were steroid-responsive. Steroid-resistant rejection occurred in 5.6% of the tacrolimus and 9.7% of the micro-CsA patients. One patient, in the micro-CsA group, experienced refractory rejection. Chronic rejection was not observed in either group. The toxicity profiles were similar. Postoperative serum creatinine levels were similar, and dialysis was required in less than 10% of patients in each group. Infectious complications were similar in both groups. Neurotoxicity was a serious adverse event in 13% and 10% of patients receiving tacrolimus and micro-CsA, respectively. Early steroid withdrawal is safe and effective after liver transplantation using either tacrolimus plus azathioprine or micro-CsA plus azathioprine immunoprophylaxis. [source] Neurotoxicity of immunosuppressive drugsLIVER TRANSPLANTATION, Issue 11 2001Eelco F.M. Wijdicks MD The clinical profile of neurotoxicity caused by immunosuppression has changed. When toxic levels are reached, both cyclosporine and tacrolimus may produce a clinical spectrum that varies from tremor and acute confusional state to status epilepticus and major speech or language abnormalities. Coma has become an unusual manifestation. Magnetic resonance imaging has been better defined, and abnormalities may be more widespread than those in the posterior lobes. These white matter lesions are caused by vasogenic edema, but may lead to apoptosis and cytotoxic edema if exposure is prolonged. Recent evidence suggests inhibition of a drug-efflux pump and dysfunction of the blood-brain barrier by enhanced nitric oxide production. [source] Tetrodotoxin-induced conduction blockade is prolonged by hyaluronic acid with and without bupivacaineACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 1 2004M. F. Stevens Background:, In isolated nerves, tetrodotoxin (TTX) blocks nerve conduction longer than bupivacaine. In vivo, however, both substances block nerve conduction to an equal duration, presumably because the hydrophilic TTX binds only weakly to the perineural tissue. High molecular weight hyaluronic acid (HA) prolongs the action of local anaesthetics several-fold. We tested whether admixture of HA enhances the binding of TTX to the perineural tissue and thus induces an ultralong conduction block after a single application. Methods:, In 12 anaesthetized rabbits, the minimal blocking concentrations of TTX, TTX and HA (TTX/HA) and bupivacaine with HA (bupivacaine/HA) were determined by blocking the natural spike activity of the aortic nerve. In 18 other animals, equipotent concentrations of either TTX, TTX/HA or TTX/bupivacaine/HA were applied topically to the aortic nerve. After disappearance of the spike activity, the wound was closed to simulate the clinical situation of a single shot nerve block. The time until recovery of spike activity was determined. The nerves were examined for signs of neurotoxicity 24 h after the application of the drugs. Data are presented as means ± SD and compared by ANOVA and Student's t -test for unpaired data. Results:, The conduction block by TTX/bupivacaine/HA (10.1 ± 1.9 h) or TTX/HA (9.3 ± 1.0 h) was significantly longer than that of plain TTX (7.9 ± 1.0 h). Neurotoxicity was not observed. Conclusions:, Both HA and HA/bupivacaine prolong the TTX-induced conduction blockade of the aortic nerve of rabbits in vivo. No signs of neurotoxicity were observed. [source] Ecotoxicity testing of chemicals with particular reference to pesticidesPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 7 2006Colin H Walker Abstract Ecotoxicity tests are performed on vertebrates and invertebrates for the environmental risk assessment of pesticides and other chemicals and for a variety of ecotoxicological studies in the laboratory and in the field. Existing practices and strategies in ecotoxicity testing are reviewed, including an account of current requirements of the European Commission for the testing of pesticides and the recent REACH (Registration, Evaluation, Authorisation and Restrictions of Chemicals) proposals for industrial chemicals. Criticisms of existing practices have been made on both scientific and ethical grounds, and these are considered before dealing with the question of possible alternative methods and strategies both for environmental risk assessment and for ecotoxicological studies more generally. New approaches from an ecological point of view are compared with recent developments in laboratory-based methods such as toxicity tests, biomarker assays and bioassays. With regard to the development of new strategies for risk assessment, it is suggested that full consideration should be given to the findings of earlier long-term studies of pollution, which identified mechanisms of action by which environmental chemicals can cause natural populations to decline. Neurotoxicity and endocrine disruption are two cases in point, and biomarker assays for them could have an important role in testing new chemicals suspected of having these properties. In a concluding discussion, possible ways of improving testing protocols are discussed, having regard for current issues in the field of environmental risk assessment as exemplified by the debate over the REACH proposals. The importance of flexibility and the roles of ecologists and ecotoxicologists are stressed in the context of environmental risk assessment. Copyright © 2006 Society of Chemical Industry [source] The Declaration of Brescia on Prevention of the Neurotoxicity of Metals,AMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 10 2007Philip Landrigan No abstract is available for this article. [source] 1,3-Diaryl-2-propenones and 2-Benzylidene-1,3-indandiones: A Quest for Compounds Displaying Greater Toxicity to Neoplasms than Normal CellsARCHIV DER PHARMAZIE, Issue 9 2010Hari N. Pati Abstract A series of 1,3-diaryl-2-propenones 2a,j and analogous 2-benzylidene-1,3-indandiones 3a,j were evaluated against various neoplasms and normal cells. In general, greater cytotoxic potencies and selective toxicity to human malignant cells were observed by the compounds in series 2 rather than 3. In particular, 2i emerged as a lead molecule having an average CC50 figure of 8.6,µM and a selective index value of 18. Various physicochemical features of 2a,j were correlated with the cytotoxic potencies to neoplastic cell lines which provide guidelines for expansion of this series of compounds. The enone 2i induced internucleosomal DNA fragmentation and activated caspase-3 in HL-60 cells suggesting that one of the ways in which the cytotoxicity of the compounds in series 2 is mediated towards some of the cell lines used in this study is by apoptosis. Neurotoxicity in mice was generally lower in series 2 than 3a,j. [source] Anticonvulsant and Neurotoxicity Evaluation of Some Novel Kojic Acids and Allomaltol DerivativesARCHIV DER PHARMAZIE, Issue 3 2010Mutlu Dilsiz Aytemir Abstract A series of new 3-hydroxy-6-hydroxymethyl/methyl-2-substituted 4H -pyran-4-ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, and ESI-MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)-induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3-hydroxy-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-6-methyl-4H -pyran-4-one (compound 1), 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-3-hydroxy-6-methyl-4H -pyran-4-one (compound 6), 2-[(4-acetyl-4-phenylpiperidin-1-yl)methyl]-3-hydroxy-6-(hydroxymethyl)-4H -pyran-4-one (compound 11), and 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl] methyl}-3-hydroxy-6-hydroxymethyl-4H -pyran-4-one (compound 12) were found to have anticonvulsant activity against MES-induced seizures at 4 h. Also, 2-{[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]methyl}-3-hydroxy-6-(hydroxymethyl)-4H -pyran-4-one (compound 8) was determined to be the most active compound against scMet-induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses. [source] Amelioration of Oxaliplatin Neurotoxicity by Drugs in Humans and Experimental Animals: A MiniReview of Recent LiteratureBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2010Badreldin H. Ali The drug is particularly useful alone and in combination with flurouracil and leucovorin in colorectal cancer, but it is also used for other cancers such as those of the ovary, lung, breast and liver, as well as non-Hodgkin's lymphoma. The drug is known to cause neurological, gastrointestinal and haematological toxicities. Neurotoxicity occurs in most of the treated patients and is considered to be a serious limitation for the use of the drug. The mechanism of the neurotoxicity is not known with certainty but may involve prolongation of sodium channels opening. Strategies to ameliorate oxaliplatin neurotoxicity include the use of several ,neuroprotective' drugs. This MiniReview attempts to list and comment on the action and use of some of these agents, which include carbamazepine, gabapentin, calcium and magnesium salts, reduced glutathione, N -acetylcysteine and a few others. None of these drugs have been proven to be effective in large, controlled, clinical trials. [source] Cyclopentenone Eicosanoids as Mediators of Neurodegeneration: A Pathogenic Mechanism of Oxidative Stress-Mediated and Cyclooxygenase-Mediated NeurotoxicityBRAIN PATHOLOGY, Issue 2 2005Erik S. Musiek The activation of cyclooxygenase enzymes in the brain has been implicated in the pathogenesis of numerous neurodegenerative conditions. Similarly, oxidative stress is believed to be a major contributor to many forms of neurodegeneration. These 2 distinct processes are united by a common characteristic: the generation of electrophilic cyclopentenone eicosanoids. These cyclopentenone compounds are defined structurally by the presence of an unsaturated carbonyl moiety in their prostane ring, and readily form Michael adducts with cellular thiols, including those found in glutathione and proteins. The cyclopentenone prostaglandins (PGs) PGA2, PGJ2, and 15-deoxy-,12,14 PGJ2, enzymatic products of cyclooxygenase-mediated arachidonic acid metabolism, exert a complex array of potent neurodegenerative, neuroprotective, and anti-inflammatory effects. Cyclopentenone isoprostanes (A2/J2 -IsoPs), products of non-enzymatic, free radical-mediated arachidonate oxidation, are also highly bioactive, and can exert direct neurodegenerative effects. In addition, cyclopentenone products of docosahexaenoic acid oxidation (cyclopentenone neuroprostanes) are also formed abundantly in the brain. For the first time, the formation and biological actions of these various classes of reactive cyclopentenone eicosanoids are reviewed, with emphasis on their potential roles in neurodegeneration. The accumulating evidence suggests that the formation of cyclopentenone eicosanoids in the brain may represent a novel pathogenic mechanism, which contributes to many neurodegenerative conditions. [source] Bortezomib is associated with better health-related quality of life than high-dose dexamethasone in patients with relapsed multiple myeloma: results from the APEX studyBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2008Stephanie J. Lee Summary Health-related quality of life (HRQL) was prospectively measured during the phase III APEX trial of bortezomib versus dexamethasone in relapsed multiple myeloma patients. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire , Core (QLQ-C30) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group,Neurotoxicity (NTX) side-effects questionnaires were administered at baseline and every 6 weeks up to 42 weeks. Patients receiving bortezomib (1·3 mg/m2, days 1, 4, 8 and 11 for eight 3-week cycles, then days 1, 8, 15 and 22 for three 5-week cycles; n = 296) demonstrated significantly better mean Global Health Status over the study versus patients receiving dexamethasone (40 mg/d, days 1,4, 9,12, and 17,20 for four 5-week cycles, then days 1,4 only for five 4-week cycles; n = 302), plus significantly better physical health, role, cognitive, and emotional functioning scores, lower dyspnoea and sleep symptom scores, and better NTX questionnaire score, using multiple imputation to account for missing data. Results were similar using available-data analyses. Sensitivity analyses suggested that improved HRQL with bortezomib is at least partially explained by improved survival. These results show that bortezomib was associated with significantly better multidimensional HRQL compared with dexamethasone, consistent with the better clinical outcomes seen with bortezomib. [source] The novel immunosuppressant SDZ-RAD protects rat brain slices from cyclosporine-induced reduction of high-energy phosphatesBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2000Natalie Serkova SDZ-RAD, 40-O-(2-hydroxyethyl)-rapamycin, is a novel macrolide immunosuppressant. Because of its synergistic interaction, SDZ-RAD is under clinical investigation as immunosuppressant in combination with cyclosporine after organ transplantation. Neurotoxicity is a critical side-effect of cyclosporine. We studied the effect of SDZ-RAD and its combination with cyclosporine on high-energy phosphates, phosphocreatine (PCr) and nucleoside triphosphates (NTP), in brain slices using 31P-magnetic resonance spectroscopy (MRS). Cyclosporine significantly reduced high-energy phosphates after 2 h in a dose-dependent manner (100 ,g l,1: 93±3% of control (NTP), 91±3% (PCr); 500 ,g l,1: 84±2% (NTP), 73±2 (PCr); 5000 ,g l,1: 68±3% (NTP), 55±5% (PCr); n=6; P<0.02). In contrast, after perfusion for 2 h, SDZ-RAD (500 ,g l,1 and 5000 ,g l,1) significantly increased high-energy phosphate concentrations in the brain slices (P<0.02). Even at the lowest concentration, SDZ-RAD protected brain energy metabolism against cyclosporine toxicity: 100 ,g l,1 SDZ-RAD+5000 ,g l,1 cyclosporine: 86±3% (NTP), 83±7% (PCr), n = 3, P<0.03 compared to cyclosporine alone. 5As evaluated using an algorithm based on Loewe isobolograms, the effects of SDZ-RAD/ cyclosporine combinations on brain energy reduction were antagonistic. Both drugs were found in mitochondria using h.p.l.c-MS analysis. We conclude that cyclosporine inhibits mitochondrial high-energy phosphate metabolism, which can be antagonized by SDZ-RAD. British Journal of Pharmacology (2000) 129, 485,492; doi:10.1038/sj.bjp.0703079 [source] Methodology for Multi-Site Ligand,Protein Docking Identification Developed for the Optimization of Spirostenol Inhibition of , -Amyloid-Induced NeurotoxicityCHEMISTRY & BIODIVERSITY, Issue 11 2005Spirostenol steroids have been found to inhibit , -amyloid-induced neurotoxicity. We have evaluated in parallel experimental and molecular-modeling studies the relative effectiveness of 17 (22R)-hydroxycholesterol derivatives in binding to the target peptide. Our results support the previous evidence that , -amyloid offers multiple docking sites for these steroids. Molecular modeling allowed for the correlation of spirostenol candidate structural differences with a choice of proposed active sites. A multi-site identification technique based on a Site-Identifier Matrix (SIM) was developed that clearly showed the uniqueness of our lead (maximum neurotoxicity inhibition) candidate SP233, with a nearly equal docking affinity for two sites. [source] Neurotoxicity by microglia: Mechanisms and potential therapeutic strategyCLINICAL AND EXPERIMENTAL NEUROIMMUNOLOGY, Issue 1 2010Hideyuki Takeuchi Abstract Microgliosis (accumulation of activated microglia) around degenerative neurons is a common pathological feature of various neurological disorders. Glutamate released by activated microglia induces excito-neurotoxicity and most likely contributes to neurodegeneration in numerous neurological diseases including ischemia, inflammation, epilepsy and neurodegenerative diseases. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for activated microglia-mediated neurodegenerative diseases, clinical trials have been failed because of adverse effects. In the present review, the neurotoxic factors from activated microglia are examined, and how these factors disturb neuronal functions is discussed. The efforts to suppress neurotoxic mechanisms by microglia are also introduced. (Clin. Exp. Neuroimmunol. doi: 10.1111/j.1759-1961.2009.00001.x, January 2010) [source] Serum or target deprivation-induced neuronal death causes oxidative neuronal accumulation of Zn2+ and loss of NAD+EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2010Christian T. Sheline Abstract Trophic deprivation-mediated neuronal death is important during development, after acute brain or nerve trauma, and in neurodegeneration. Serum deprivation (SD) approximates trophic deprivation in vitro, and an in vivo model is provided by neuronal death in the mouse dorsal lateral geniculate nucleus (LGNd) after ablation of the visual cortex (VCA). Oxidant-induced intracellular Zn2+ release ([Zn2+]i) from metallothionein-3 (MT-III), mitochondria or ,protein Zn2+', was implicated in trophic deprivation neurotoxicity. We have previously shown that neurotoxicity of extracellular Zn2+ required entry, increased [Zn2+]i, and reduction of NAD+ and ATP levels causing inhibition of glycolysis and cellular metabolism. Exogenous NAD+ and sirtuin inhibition attenuated Zn2+ neurotoxicity. Here we show that: (1) Zn2+ is released intracellularly after oxidant and SD injuries, and that sensitivity to these injuries is proportional to neuronal Zn2+ content; (2) NAD+ loss is involved , restoration of NAD+ using exogenous NAD+, pyruvate or nicotinamide attenuated these injuries, and potentiation of NAD+ loss potentiated injury; (3) neurons from genetically modified mouse strains which reduce intracellular Zn2+ content (MT-III knockout), reduce NAD+ catabolism (PARP-1 knockout) or increase expression of an NAD+ synthetic enzyme (Wlds) each had attenuated SD and oxidant neurotoxicities; (4) sirtuin inhibitors attenuated and sirtuin activators potentiated these neurotoxicities; (5) visual cortex ablation (VCA) induces Zn2+ staining and death only in ipsilateral LGNd neurons, and a 1 mg/kg Zn2+ diet attenuated injury; and finally (6) NAD+ synthesis and levels are involved given that LGNd neuronal death after VCA was dramatically reduced in Wlds animals, and by intraperitoneal pyr vate or nicotinamide. Zn2+ toxicity is involved in serum and trophic deprivation-induced neuronal death. [source] The concentration of hydrogen peroxide generated during aggregation of ,-synuclein in vitro is lower than 5 nmol/LCHINESE JOURNAL OF CHEMISTRY, Issue 12 2004Li-Na Ji Abstract Using a fluorometric method with a detection limit of 5 nmol/L. here it is reported that albeit positive results were got from bovine serum albumin (BSA) and chicken ovalbumin (OVA) as published in literature, no detectable amount of hydrogen peroxide (H2O2) was generated during ,-synuclein (,-Syn) aggregation in vitro even in the presence of transition metal ions Cu(II) or Fe(III). The results suggest that the concentration of H2O2 generated during aggregation of ,-Syn in vitro be lower than 5 nmol/L beyond the detection limit of the adopted method and it is far too poor to be responsible for the cytotoxicity of ,-Syn aggregates, thus allowing people to extensively elucidate the mechanism underlying neurotoxicities of the aggregates formed by some amyloidogenic proteins. [source] Ethanol neurotoxicity and dentate gyrus developmentCONGENITAL ANOMALIES, Issue 3 2008Takanori Miki ABSTRACT Maternal alcohol ingestion during pregnancy adversely affects the developing fetus, often leading to fetal alcohol syndrome (FAS). One of the most severe consequences of FAS is brain damage that is manifested as cognitive, learning, and behavioral deficits. The hippocampus plays a crucial role in such abilities; it is also known as one of the brain regions most vulnerable to ethanol-induced neurotoxicity. Our recent studies using morphometric techniques have further shown that ethanol neurotoxicity appears to affect the development of the dentate gyrus in a region-specific manner; it was found that early postnatal ethanol exposure causes a transitory deficit in the hilus volume of the dentate gyrus. It is strongly speculated that such structural modifications, even transitory ones, appear to result in developmental abnormalities in the brain circuitry and lead to the learning disabilities observed in FAS children. Based on reports on possible factors deciding ethanol neurotoxicity to the brain, we review developmental neurotoxicity to the dentate gyrus of the hippocampal formation. [source] Principles of risk assessment for determining the safety of chemicals: Recent assessment of residual solvents in drugs and di(2-ethylhexyl) phthalateCONGENITAL ANOMALIES, Issue 2 2004Ryuichi Hasegawa ABSTRACT Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose,response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose,response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established ,safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity. [source] Pharmacogenetics of the neurodevelopmental impact of anticancer chemotherapyDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 3 2008Philippe Robaey Abstract Pharmacogenetics holds the promise of minimizing adverse neurodevelopmental outcomes of cancer patients by identifying patients at risk, enabling the individualization of treatment and the planning of close follow-up and early remediation. This review focuses first on methotrexate, a drug often implicated in neurotoxicity, especially when used in combination with brain irradiation. The second focus is on glucocorticoids that have been found to be linked to adverse developmental effects in relation with the psychosocial environment. For both examples, we review how polymorphisms of genes encoding enzymes involved in specific mechanisms of action could moderate adverse neurodevelopmental consequences, eventually through common final pathways such as oxidative stress. We discuss a multiple hit model and possible strategies required to rise to the challenge of this integrative research. © 2008 Wiley-Liss, Inc. Dev Disabil Res Rev 2008;14:211,220. [source] Delayed neurotoxicity associated with therapy for children with acute lymphoblastic leukemiaDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 3 2006Peter D. Cole Abstract Most children diagnosed today with acute lymphoblastic leukemia (ALL) will be cured. However, treatment entails risk of neurotoxicity, causing deficits in neurocognitive function that can persist in the years after treatment is completed. Many of the components of leukemia therapy can contribute to adverse neurologic sequelae, including craniospinal irradiation, nucleoside analogs, corticosteroids, and antifolates. In this review, we describe the characteristic radiographic findings and neurocognitivie deficits seen among survivors of childhood ALL. We summarize what is known about the pathophysiology of delayed treatment-related neurotoxicity, with a focus on the toxicity resulting from pharmacologic disruption of folate physiology within the central nervous system. Finally, we suggest testable strategies to ameliorate the symptoms of treatment-related neurotoxicity or decrease its incidence. MRDD Research Reviews 2006;12:174,183. © 2006 Wiley-Liss, Inc. [source] Intrastriatal administration of human immunodeficiency virus-1 glycoprotein 120 reduces glial cell-line derived neurotrophic factor levels and causes apoptosis in the substantia nigraDEVELOPMENTAL NEUROBIOLOGY, Issue 12 2006Rachel L. Nosheny Abstract Uninfected neurons of the substantia nigra (SN) degenerate in human immunodeficiency virus (HIV)-positive patients through an unknown etiology. The HIV envelope glycoprotein 120 (gp120) causes apoptotic neuronal cell death in the rodent striatum, but its primary neurotoxic mechanism is still under investigation. Previous studies have shown that gp120 causes neurotoxicity in the rat striatum by reducing brain-derived neurotrophic factor (BDNF). Because glial cell line-derived neurotrophic factor (GDNF) and BDNF are neurotrophic factors crucial for the survival of dopaminergic neurons of the SN, we investigated whether gp120 reduces GDNF and BDNF levels concomitantly to induce apoptosis. Rats received a microinjection of gp120 or vehicle into the striatum and were sacrificed at various time intervals. GDNF but not BDNF immunoreactivity was decreased in the SN by 4 days in gp120-treated rats. In these animals, a significant increase in the number of caspase-3- positive neurons, both tyrosine hydroxylase (TH)-positive and -negative, was observed. Analysis of TH immunoreactivity revealed fewer TH-positive neurons and fibers in a medial and lateral portion of cell group A9 of the SN, an area that projects to the striatum, suggesting that gp120 induces retrograde degeneration of nigrostriatal neurons. We propose that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor expression by gp120. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Methanol exposure interferes with morphological cell movements in the Drosophila embryo and causes increased apoptosis in the CNSDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2004Dervla M. Mellerick Abstract Despite the significant contributions of tissue culture and bacterial models to toxicology, whole animal models for developmental neurotoxins are limited in availability and ease of experimentation. Because Drosophila is a well understood model for embryonic development that is highly accessible, we asked whether it could be used to study methanol developmental neurotoxicity. In the presence of 4% methanol, approximately 35% of embryos die and methanol exposure leads to severe CNS defects in about half those embryos, where the longitudinal connectives are dorsally displaced and commissure formation is severely reduced. In addition, a range of morphological defects in other germ layers is seen, and cell movement is adversely affected by methanol exposure. Although we did not find any evidence to suggest that methanol exposure affects the capacity of neuroblasts to divide or induces inappropriate apoptosis in these cells, in the CNS of germ band retracted embryos, the number of apoptotic nuclei is significantly increased in methanol-exposed embryos in comparison to controls, particularly in and adjacent to the ventral midline. Apoptosis contributes significantly to methanol neurotoxicity because embryos lacking the cell death genes grim, hid, and reaper have milder CNS defects resulting from methanol exposure than wild-type embryos. Our data suggest that when neurons and glia are severely adversely affected by methanol exposure, the damaged cells are cleared by apoptosis, leading to embryonic death. Thus, the Drosophila embryo may prove useful in identifying and unraveling mechanistic aspects of developmental neurotoxicity, specifically in relation to methanol toxicity. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 308,318, 2004 [source] | ||||||||||||||||||||||||||||||||||