Acute Neurotoxicity Research Articles

To Break or to Brake Neuronal Network Accelerated by Ammonium Ions?

PurposeThe aim of present study was to investigate the effects of ammonium ions on in vitro neuronal network activity and to search alternative methods of acute ammonia neurotoxicity prevention.MethodsRat hippocampal neuronal and astrocytes co-cultures in vitro, fluorescent microscopy and perforated patch clamp were used to monitor the changes in intracellular Ca2+- and membrane potential produced by ammonium ions and various modulators in the cells implicated in neural networks.ResultsLow concentrations of NH4Cl (0.1–4 mM) produce short temporal effects on network activity. Application of 5–8 mM NH4Cl: invariably transforms diverse network firing regimen to identical burst patterns, characterized by substantial neuronal membrane depolarization at plateau phase of potential and high-amplitude Ca2+-oscillations; raises frequency and average for period of oscillations Ca2+-level in all cells implicated in network; results in the appearance of group of «run out» cells with high intracellular Ca2+ and steadily diminished amplitudes of oscillations; increases astrocyte Ca2+-signalling, characterized by the appearance of groups of cells with increased intracellular Ca2+-level and/or chaotic Ca2+-oscillations. Accelerated network activity may be suppressed by the blockade of NMDA or AMPA/kainate-receptors or by overactivation of AMPA/kainite-receptors. Ammonia still activate neuronal firing in the presence of GABA(A) receptors antagonist bicuculline, indicating that «disinhibition phenomenon» is not implicated in the mechanisms of networks acceleration. Network activity may also be slowed down by glycine, agonists of metabotropic inhibitory receptors, betaine, L-carnitine, L-arginine, etc.ConclusionsObtained results demonstrate that ammonium ions accelerate neuronal networks firing, implicating ionotropic glutamate receptors, having preserved the activities of group of inhibitory ionotropic and metabotropic receptors. This may mean, that ammonia neurotoxicity might be prevented by the activation of various inhibitory receptors (i.e. by the reinforcement of negative feedback control), instead of application of various enzyme inhibitors and receptor antagonists (breaking of neural, metabolic and signaling systems).

Quantitative Sensory Testing at Baseline and During Cycle 1 Oxaliplatin Infusion Detects Subclinical Peripheral Neuropathy and Predicts Clinically Overt Chronic Neuropathy in Gastrointestinal Malignancies

PurposeOxaliplatin neurotoxicity has a spectrum of manifestations from an often reversible acute neurotoxicity to a more irreversible “stocking and glove” chronic neuropathy that is associated with high morbidity. Quantitative sensory testing (QST) is a noninvasive psychometric testing method that can potentially be used in the clinic setting to measure subclinical neurologic changes early on to identify patients that will experience chronic oxaliplatin-induced peripheral neuropathy at 1 year. Patients and MethodsThirty patients with gastrointestinal malignancies who were receiving oxaliplatin were recruited. QST and patient-reported outcomes were assessed at baseline; during infusion cycles 1, 2, 4, and 6; and at 1 year. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0, chronic neuropathy scores were assessed at the 1-year time point. The variables at each time point were evaluated for prediction of 1-year chronic neuropathy scores. ResultsWe found that patients with preexisting subclinical neuropathy were more likely to experience grades 2 and 3 chronic neuropathy than were those who did not have this condition (heat detection threshold, Spearman correlation coefficient (rs) = 0.39; P = .037; pellet retrieval time, rs = 0.47; P = .024). Patients in whom thermal and cutaneous sensory deficits developed with cycle 1 infusion were also more likely to experience grades 2 and 3 neuropathy at 1 year (cold detection threshold, rs = 0.50; P = .007; heat detection threshold, rs = 0.39; P = .042; cutaneous detection threshold, rs = 0.42; P = .043). ConclusionQST provides a noninvasive, commercially available, and feasible clinical test to select patients, even before oxaliplatin treatment, who are likely to experience moderate to severe chronic peripheral neuropathy.

C-Phycocyanin protects against acute tributyltin chloride neurotoxicity by modulating glial cell activity along with its anti-oxidant and anti-inflammatory property: A comparative efficacy evaluation with N-acetyl cysteine in adult rat brain

Spirulina is a widely used health supplement and is a dietary source of C-Phycocyanin (CPC), a potent anti-oxidant. We have previously reported the neurotoxic potential of tributyltin chloride (TBTC), an environmental pollutant and potent biocide. In this study, we have evaluated the protective efficacy of CPC against TBTC induced neurotoxicity. To evaluate the extent of neuroprotection offered by CPC, its efficacy was compared with the degree of protection offered by N-acetylcysteine (NAC) (a well known neuroprotective drug, taken as a positive control). Male Wistar rats (28day old) were administered with 20mg/kg TBTC (oral) and 50mg/kg CPC or 50mg/kg NAC (i.p.), alone or in combination, and various parameters were evaluated. These include blood–brain barrier (BBB) damage; redox parameters (ROS, GSH, redox pathway associated enzymes, oxidative stress markers); inflammatory, cellular, and stress markers; apoptotic proteins and in situ cell death assay (TUNEL). We observed increased CPC availability in cortical tissue following its administration. Although BBB associated proteins like claudin-5, p-glycoprotein and ZO-1 were restored, CPC/NAC failed to protect against TBTC induced overall BBB permeability (Evans blue extravasation). Both CPC and NAC remarkably reduced oxidative stress and inflammation. NAC effectively modulated redox pathway associated enzymes whereas CPC countered ROS levels efficiently. Interestingly, CPC and NAC were equivalently capable of reducing apoptotic markers, astroglial activation and cell death. This study illustrates the various pathways involved in CPC mediated neuroprotection against this environmental neurotoxicant and highlights its capability to modulate glial cell activity.

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats.

Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia.

Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus.

The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer’s disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca2+ and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca2+-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.

The role of multifunctional drug therapy against carbamate induced neuronal toxicity during acute and chronic phase in rats

The current study has been designed to examine the effect of multifunctional drug therapy on carbofuran induced acute (2.187mg/kg, s.c.) and sub-acute (0.2187mg/kg, s.c.) neurotoxicity in male wistar rats. Drug treatment which includes nimodipine (Ca2+ channel blocker), diazepam, ropinirole (dopamine agonist) and GSPE (antioxidant) was started 2h after carbofuran administration. Morris water maze was employed for aiming spatial memory. Narrow beam walk and rotarod were employed for testing motor functions. Brain acetylcholinesterase activity, thiobarbituric acid reactive species, nitrite, reduced glutathione, catalase levels, and mitochondrial complexes were also estimated. Carbofuran treatment resulted in significant development of cognitive and motor functions manifested as impairment in learning and memory along with increased thiobarbituric acid reactive species, nitrite levels and decreased acetylcholinesterase activity, reduced glutathione, catalase levels, and mitochondrial complexes. The standard antidote therapy (atropine) was not able to provide neuroprotection but was able to provide symptomatic relief. The multifunctional drug therapy attenuated carbofuran induced cognitive and motor dysfunction, acetylcholinesterase activity and other biochemical parameters. The triple combination in sub-acute study may be avoided in future as two drug combinations provide adequate neuroprotection. Thus it can be concluded that standard antidotal therapy may not provide neuroprotection while the multifunctional drug therapy offers neuroprotection against carbofuran and may dramatically increase survival and life quality.

Assessment of acute oxaliplatin-induced cold allodynia: a pilot study.

Following oxaliplatin treatment, acute neurotoxicity symptoms are suggested to be correlated with both the development and degree of chronic neuropathy. The aim of this clinical commentary was to examine different methods to assess acute cold allodynia and dysesthesia in patients treated with adjuvant oxaliplatin. Nine patients over the age of 18years scheduled for standard adjuvant treatment with capecitabine and oxaliplatin were included. Patients were asked to come for two visits: a baseline visit before and a follow-up visit within 5days after treatment. Patients were examined with questionnaires, thermal tests, and the thermal grill. All patients reported neurotoxicity, and they all had abnormal cold sensitivity. The only significant changes observed were increased ratings of pain, unpleasantness, and pricking sensations to holding a ~8°C metal cylinder for 10s and an increased intensity of unpleasantness and pricking sensation to the 20-s contact with the 10°C plates of the thermal grill on the palmar hand. he results showed that the palm of the hand is the most sensitive part of the body when detecting oxaliplatin-induced cold allodynia, and the use of a cold metal cylinder seems as a promising sensitive method.

Updates on Oxaliplatin-Induced Peripheral Neurotoxicity (OXAIPN).

Oxaliplatin-induced peripheral neuropathy (OXAIPN) is of great clinical interest as it ranks among the most common dose limiting toxicities of oxaliplatin (OXA) administration with an obvious impact on the outcome of cancer patients. In addition, OXAIPN has a detrimental effect on the quality of life of cancer patients because it can be long lasting or even permanent. It has a unique spectrum of clinical presentation, being manifested with two distinct syndromes: the acute neurotoxicity that appears soon after OXA administration and is usually transient, and the chronic cumulative syndrome that resembles the characteristics of all platinum compounds. Despite advances in research in relation to the elucidation of the true OXAIPN pathogenesis, characteristics and management, there are still several open issues to be addressed. One of the most important open issues is to determine reliable biomarkers to allow prompt identification of patients at high risk to develop OXAIPN and towards this view well designed genome wide analyses are warranted to adequately address this gap in knowledge. Recent updates are provided in this article in relation to the pathogenesis, clinical characteristics, pharmacogenetics and management of OXAIPN.

Adverse outcome pathway on: Binding of pyrethroids to voltage-gated sodium channels induces acute neurotoxicity

Adverse outcome pathway on: Binding of pyrethroids to voltage-gated sodium channels induces acute neurotoxicity

Screening the ToxCast Phase I and II libraries for acute neurotoxicity using cortical neurons grown on multi-well microelectrode array (mwMEA) plates

Screening the ToxCast Phase I and II libraries for acute neurotoxicity using cortical neurons grown on multi-well microelectrode array (mwMEA) plates

Platinum-induced neurotoxicity and preventive strategies: past, present, and future.

Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution.

Design, synthesis and pharmacological evaluation of novel N-(2-(1, 1-dimethyl-5, 7-dioxo-4, 6-diazaspiro[2.4]heptan-6-yl)ethyl) sulfonamide derivatives as potential anticonvulsant agents

A series of new N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl) sulfonamide derivatives (8a-i) and ethyl 2,2-dimethyl-1-(3-(2-(sulfonamido)ethyl)ureido) cyclopropanecarbox-ylate derivatives (9a-i) were designed, synthesized and evaluated for their anticonvulsant activities using maximal electroshock shock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4-fluoroben- zenesulfonamide (8f) and N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4- methylbenzenesulfonamide (8e) have shown promising anticonvulsant activities in MES model. The most active compound 8f has shown the MES-induced seizures with ED50 value of 28.05 mg/kg and TD50 value of 561 mg/kg after intraperitoneal injection to mice, which provided compound 8f with a protective index (TD50/ED50) of 20 in the MES test. Further, rotarod toxicity method was used to study the acute neurotoxicity profile of selected compounds.

Benefits of minimizing immunosuppressive dosage according to cytochrome P450 3A5 genotype in liver transplant patients: findings from a single-center study.

We evaluated the clinical efficacy of tailoring tacrolimus dosage to cytochrome P450 (CYP) 3A5 genotype in liver transplant patients. One hundred patients who received tacrolimus-based therapy were included in the retrospective study in which the relationship between the tacrolimus blood trough concentration/dosage ratio and the CYP3A5 genotype of both donors and recipients was determined. Subsequently, 106 patients were continuously enrolled in a prospective study and followed-up for 6 months; the relationship between tacrolimus dosage and CYP3A5 genotype was also determined. Rates of acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, and hyperglycemia were compared between the groups. During the 6 months following liver transplantation, the mean tacrolimus concentration/dosage ratio among patients who did not have the CYP3A5*1 genotype and who received a transplant from a donor with the same genotype (24/100, 24% of patients) was higher than that among patients who did have the CYP3A5*1 genotype and/or had a donor with the same genotype (76/100, 76% of patients). In the second part of the study, the tacrolimus dosage was tailored to CYP3A5 genotype and 24 patients (22.64%) received a lower dose. There was an obvious decrease in acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, hyperglycemia, and Pneumocystis carinii infection among the latter group. A lower tacrolimus dose was suitable for about 25% of the liver transplant patients, as these patients did not have the CYP3A5*1 genotype and received a transplant from a donor with the same genotype. Tailoring the tacrolimus dosage according to the CYP3A5 genotype could reduce rejection and adverse effects.

The Evaluation of the Potency of Newly Developed Oximes (K727, K733) and Trimedoxime to Counteract Acute Neurotoxic Effects of Tabun in Rats.

The ability of two newly developed oximes (K727, K733) to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 µg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge. All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings.

Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer.

KRAS mutations are a major cause of drug resistance to molecular-targeted therapies. Aberrant epidermal growth factor receptor (EGFR) signaling may cause dysregulation of microRNA (miRNA) and gene regulatory networks, which leads to cancer initiation and progression. To address the functional relevance of miRNAs in mutant KRAS cancers, we transfected exogenous KRASG12V into human embryonic kidney 293 and MRC5 cells with wild-type KRAS and BRAF genes, and we comprehensively profiled the dysregulated miRNAs. The result showed that mature miRNA oligonucleotide (miR)-4689, one of the significantly down-regulated miRNAs in KRASG12V overexpressed cells, was found to exhibit a potent growth-inhibitory and proapoptotic effect both in vitro and in vivo. miR-4689 expression was significantly down-regulated in cancer tissues compared to normal mucosa, and it was particularly decreased in mutant KRAS CRC tissues. miR-4689 directly targets v-ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) and v-akt murine thymoma viral oncogene homolog 1(AKT1), key components of two major branches in EGFR pathway, suggesting KRAS overdrives this signaling pathway through inhibition of miR-4689. Overall, this study provided additional evidence that mutant KRAS functions as a broad regulator of the EGFR signaling cascade by inhibiting miR-4689, which negatively regulates both RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. These activities indicated that miR-4689 may be a promising therapeutic agent in mutant KRAS CRC.

Agmatine prevents acute chlorpromazine-induced neurotoxicity in rats

The present study was directed to potentially beneficial effects of agmatine (AGM) on oxidative/nitrosative stress development in selective vulnerable brain regions during chlorpromazine (HPZ) treatment in rats. All tested compounds were administered intraperitoneally (i.p.) in one single dose. The animals were divided into control (K, 0.9 % saline solution), HPZ (HPZ, 38.7 mg/kg b.w.), HPZ+AGM (AGM, 75 mg/kg b.w. immediately after HPZ, 38.7 mg/kg b.w. i.p.) and AGM (AGM, 75 mg/kg b.w.) groups. Rats were sacrificed by decapitation 24 hours after the treatment. Analysis of data showed that HPZ+AGM injection significantly decreased drug concentration compared with HPZ-animals (p<0.05). HPZ application increased lipid peroxidation (p<0.001 in cortex, striatum and hippocampus), nitrite and nitrate concentration (p<0.001 in all three brain regions) and superoxide anion production (p<0.05 in all three brain structures), while completely damaged enzymatic antioxidative defense system (superoxide dismutase in both cortex and striatum p<0.05 and hippocampus p<0.001; glutathion reductase in both cortex and striatum p<0.001 and hippocampus p<0.05; catalase in cortex p<0.001 and both striatum and hippocampus p<0.05). However, treatment with AGM significantly attenuated the oxidative stress parameters compared to HPZ-group (lipid peroxidation in cortex p<0.001, striatum p<0.01 and hippocampus p<0.05; nitrite and nitrate concentration in all three brain structures p<0.001) and restores antioxidant capacity to control values in all examined brain structures. Immunohistochemical staining of GFAP molecules in rats showed an increase in the number of positive cells 24 h after acute HPZ-administration. All these results indicate that AGM may be effective in the protection of HPZ-induced brain injury in rats.

Chapter 7 - Neurotoxicity of solvents

Worldwide, several hundred million tons of organic solvents are used annually in household, industry, and other occupational settings. Millions of workers are regularly exposed to organic solvents considered neurotoxic. Acute neurotoxicity due to high exposure of solvent is usually evident, but the nature of long-term effects, such as chronic solvent encephalopathy (CSE), has raised uncertainty even among experts. Earlier studies were criticized for their methodology, mainly epidemiologic studies or investigations of exposed groups with many possible confounders and inadequate exposure assessment. However, an increasing number of studies have been performed since, also on workers with defined CSE based on differential diagnostics. During the last decade, evidence has emerged to enable identification of CSE, a necessity for the early recognition and prevention of progression of dysfunction and disability. Selected chemicals are presented here due to their widespread use, neurotoxic potential, and ability to cause solvent encephalopathy. Constant introduction of new chemicals may introduce new hazardous chemicals or known chemicals may reveal new health effects. It is important to keep an open mind for new findings of solvent-related neurobehavioral effects.

Sedaxane

The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of sedaxane (CAS No.874967–67-6), a pyrazole carboxamide fungicide, based on results from various studies. Major adverse effects of sedaxane observed are decreased body weight gain, decrease in food intake, and centrilobular hepatocellular hypertrophy. Sedaxane did not show any neurotoxicity, teratogenicity, reproductive toxicity, genotoxicity and immunotoxicity. In a two-year combined chronic toxicity/carcinogenicity study in rats, increased incidence of uterine adenocarcinomas was observed. Increased incidence of hepatocellular tumors was also observed in an 80-week carcinogenicity test in mice. However, a genotoxic mechanism was unlikely to be involved in the tumor induction. It was thus considered possible to establish a threshold in the assessment. Based on the above results, only sedaxane (parent compound) was identified as the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) in the toxicological studies was 11 mg/kg bw/day in a combined two-year chronic toxicity/carcinogenicity study in rats. Applying a safety factor of 100 to the NOAEL, FSCJ specified the acceptable daily intake (ADI) of 0.11 mg/kg bw/day. The lowest NOAEL for adverse effects resulted from a single oral administration of sedaxane was 30 mg/kg bw observed in an acute neurotoxicity study in rats. Applying a safety factor of 100 to the NOAEL, FSCJ specified 0.3 mg/kg bw as the acute reference dose (ARfD).

Picoxystrobin

The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of picoxystrobin (CAS No. 117428-22-5), a strobilurin fungicide, based on results from various studies. Major adverse effects of picoxystrobin observed are decreased body weight gain, hepatocellular hypertrophy in mice, as well as mucosal hyperplasia and dilated mucosal gland of the duodenum in mice. No neurotoxicity, reproductive toxicity, teratogenicity, immunotoxicity or genotoxicity relevant to human health were observed. Although increased incidences of interstitial cell adenomas were observed in a two-year chronic toxicity/carcinogenicity study in rats, genotoxic mechanism was unlikely to be involved in the tumor induction, and therefore, FSCJ concluded that it is possible to establish a threshold dose in the assessment. Based on the above results, only picoxystrobin (parent compound) was identified as the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained was 4.6 mg/kg bw/day in a one-year chronic toxicity study in dogs. FSCJ specified the acceptable daily intake (ADI) of 0.046 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. In an acute neurotoxicity study in rats, NOAEL was not obtained, but the lowest-observed-adverse-effect level (LOAEL) was 200 mg/kg bw. In developmental toxicity studies, NOAELs obtained for adverse effects possibly caused by a single oral administration of picoxystrobin were 25 mg/kg bw/day in rabbits and 30 mg/kg bw/day in rats. Considering those results comprehensively, FSCJ specified an acute reference dose (ARfD) of 0.2 mg/kg bw based on the LOAEL of 200 mg/kg bw obtained from an acute neurotoxicity study in rats, applying a safety factor of 1,000 (10 for species difference, 10 for individual difference, and 10 for the adopted LOAEL value).

Cerium and yttrium oxide nanoparticles against lead-induced oxidative stress and apoptosis in rat hippocampus.

Due to numerous industrial applications, lead has caused widespread pollution in the environment; it seems that the central nervous system (CNS) is the main target for lead in the human body. Oxidative stress and programmed cell death in the CNS have been assumed as two mechanisms related to neurotoxicity of lead. Cerium oxide (CeO2) and yttrium oxide (Y2O3) nanoparticles have recently shown antioxidant effects, particularly when used together, through scavenging the amount of reactive oxygen species (ROS) required for cell apoptosis. We looked into the neuroprotective effects of the combinations of these nanoparticles against acute lead-induced neurotoxicity in rat hippocampus. We used five groups in this study: control, lead, CeO2 nanoparticles + lead, Y2O3 nanoparticles + lead, and CeO2 and Y2O3 nanoparticles + lead. Nanoparticles of CeO2 (1000 mg/kg) and Y2O3 (230 mg/kg) were administered intraperitoneally during 2 days prior to intraperitoneal injection of the lead (25 mg/kg for 3 days). At the end of the treatments, oxidative stress markers, antioxidant enzymes activity, and apoptosis indexes were investigated. The results demonstrated that pretreatments with CeO2 and/or Y2O3 nanoparticles recovered lead-caused oxidative stress markers (ROS, lipid peroxidation, and total thiol molecules) and apoptosis indexes (Bax/Bcl-2 and caspase-3 protein expression). Besides, these nanoparticles reduced the activities of lead-induced superoxide dismutase and catalase as well as the ADP/ATP ratio. Interestingly, the best recovery resulted from the compound of these nanoparticles. Based on these outcomes, it appears that this combination may potentially be beneficial for protection against lead-caused acute toxicity in the brain through improving the oxidative stress-mediated programmed cell death pathway.