phosphinothricin and Seizures

Exposure to pesticides can induce neurobehavioral effects in rodents, as well as in other mammals, including humans. However, the effects of the toxicity of pesticides on the central nervous system (CNS) remain largely unclear. The expression of the activity-regulated cytoskeleton-associated protein gene (Arc) is induced in a neuronal-activity-dependent manner and is implicated in synaptic and experience-dependent plasticity. We previously developed Arc-promoter-driven luciferase transgenic (Tg) mouse strains to monitor the neuronal-activity-dependent gene expression under physiological and pathological conditions in vivo. In this study, we examined the effect of acute administration of four different pesticides (deltamethrin, glufosinate, methylcarbaryl, and imidacloprid) on neuronal activity using Arc-Luc Tg mice. The change in the bioluminescence signal in mouse brain upon treatment with deltamethrin and glufosinate occurred more slowly than that of kainic acid, a potent neuroexcitatory amino acid agonist. These two pesticides also caused convulsive responses in adult Arc-Luc Tg mice. In the case of glufosinate, we detected the long-term upregulation of bioluminescence signal intensity of Arc-Luc over 24 h after the treatment. Furthermore, we observed greater changes of bioluminescence signal in adults than in juveniles, and a lower incidence of convulsions at the juvenile stage. In contrast to the acute treatment, we detected a decrease of bioluminescence signal after low-dose chronic treatment with glufosinate, without neuronal overexcitation. From these results, we suggest that Arc-Luc Tg mice are useful for assessing the acute and chronic effects of pesticides on the CNS.

Topics: Aminobutyrates; Animals; Brain; Convulsants; Cytoskeletal Proteins; Luminescent Measurements; Mice, Transgenic; Neonicotinoids; Nerve Tissue Proteins; Nitriles; Nitro Compounds; Pesticides; Pyrethrins; Seizures

The incidence and clinical aspects of seizures remain to be elucidated in patients with acute pesticide intoxication. The present study included subjects who ingested pesticide with the intention of committing suicide and were treated at Soonchunhyang University Hospital (Cheonan, Korea) between January 2011 and December 2014. We analyzed the incidence and characterized the type and frequency of seizure, from the medical records of 464 patients with acute pesticide intoxication, according to the pesticide class. The effect of seizure on the clinical outcome was assessed. The incidence of seizure was 31.5% in patients who ingested glufosinate ammonium {2-amino-4-[hydroxyl (methyl) phosphinoyl] butyrate; ammonium DL-homoalanin-4-yl (methyl) phosphinate}, followed by those who ingested pyrethroid (5.9%) or glycine derivatives (5.4%). All of the seizures developed between 12 and 24 h of pesticide ingestion and had ceased by 72 h after seizure initiation, following treatment with antiseizure medication. Generalized tonic-clonic seizures were the most commonly observed (85.7% of the cases). Multivariable logistic regression analysis showed that the effect of seizure on mortality was not statistically significant. In conclusion, glufosinate ammonium herbicide is the most common seizurogenic pesticide class. Seizure itself was not a risk factor for mortality in patients with acute glufosinate ammonium intoxication.

Topics: Adult; Aged; Aminobutyrates; Anticonvulsants; Chi-Square Distribution; Female; Glycine; Herbicides; Hospitals, University; Humans; Incidence; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neurotoxicity Syndromes; Pyrethrins; Republic of Korea; Risk Factors; Seizures; Suicide, Attempted; Time Factors; Treatment Outcome

Central nervous system (CNS) complications such as seizures and reduced consciousness are important in glufosinate and may occur in severe glyphosate poisoning. The aim of this study was to assess the possible role of serum S100B protein as a biochemical marker of CNS complications associated with glyphosate or glufosinate poisoning.. The study enrolled 40 patients (23 glyphosate poisoning and 17 glufosinate poisoning). Altered consciousness and seizure were observed during hospitalization. S100B level was measured with fully automated modular analytic E170 system using electrochemoluminometric immunoassay.. Among 40 patients, neurologic features were observed in 12 patients with a median time to onset of 21.5 (IQR 8.25-24.75) h. Serum S100B concentrations measured on admission were higher in the group with neurologic features than in the group without neurologic features [0.148 μg/L (IQR 0.128-0.248) vs. 0.072 μg/L (IQR 0.047-0.084), p < .001]. Univariate analysis of measured patient raw parameters using a ROC curve showed that S100B was a significant predictor of neurologic features in glyphosate and glufosinate poisoning. The area under the ROC curve was 0.894 (95% confidential interval 0.791-0.998). When S100B was set at 0.0965, its sensitivity and specificity for predicting neurologic features in glyphosate and glufosinate poisoning were 92% and 82%, respectively.. In our pilot study, S100B was a significant predictor of neurologic complications in patients with glyphosate and glufosinate poisoning. Large prospective cohorts are needed to confirm this finding.

Topics: Adult; Aged; Aminobutyrates; Biomarkers; Consciousness; Glycine; Glyphosate; Humans; Logistic Models; Middle Aged; Nervous System Diseases; Pilot Projects; Poisoning; Prospective Studies; ROC Curve; S100 Proteins; Seizures; Sensitivity and Specificity

Glufosinate poisoning can cause neurologic complications that may be difficult to treat due to delayed manifestation. Studies assessing possible predictors of complications are lacking. Although serum ammonia level is a potential predictor of severe neurotoxicity, it has only been assessed via case reports. Therefore, we investigated factors that predict neurologic complications in acute glufosinate-poisoned patients.. We conducted a retrospective review of 45 consecutive glufosinate-poisoning cases that were diagnosed in the emergency department (ED) of Wonju Severance Christian Hospital between May 2007 and July 2014. Patients with a Glasgow Coma Scale (GCS) score of <8, seizure, and/or amnesia were defined to a neurologic complication group.. The neurologic complication group (29 patients, 64.4%) comprised patients with GCS<8 (27 patients, 60.0%), seizure (23 patients, 51.1%), and amnesia (5 patients, 11.1%). Non-neurologic complications included respiratory failure (14 patients, 31.1%), intubation and ventilator care (23 patients, 51.1%), shock (2 patients, 4.4%), pneumonia (16 patients, 35.6%), acute kidney injury (10 patients, 22.2%), and death (4 patients, 8.9%). Complications of GCS<8, seizure, respiratory failure, and intubation and ventilator care appeared during latent periods within 11 hrs, 34 hrs, 14 hrs, and 48 hrs, respectively. Initial serum ammonia was a predictor of neurologic complications [odds ratio 1.039, 95% confidence interval (1.001-1.078), p=0.046 and area under the curve 0.742].. Neurologic complications developed in 64.4% of patients with acute glufosinate poisoning. The most common complication was GCS<8. Initial serum ammonia level, which can be readily assessed in the ED, was a predictor of neurologic complications.

Topics: Adult; Aged; Aged, 80 and over; Aminobutyrates; Ammonia; Emergency Service, Hospital; Female; Glasgow Coma Scale; Humans; Male; Middle Aged; Nausea; Neurotoxicity Syndromes; Respiratory Insufficiency; Retrospective Studies; Seizures; Severity of Illness Index; Vomiting

Glufosinate-ammonium (GLA), the active component of a widely used herbicide, induces convulsions in rodents and humans. In mouse, intraperitoneal treatment with 75 mg/kg GLA generates repetitive tonic-clonic seizures associated with 100% mortality within 72 h after treatment. In this context, we characterized GLA-induced seizures, their histological consequences and the effectiveness of diazepam treatment. Epileptic discharges on electroencephalographic recordings appeared simultaneously in the hippocampus and the cerebral cortex. Diazepam treatment at 6 h immediately stopped the seizures and prevented animal death. However, intermittent seizures were recorded on electroencephalogram from 6 h after diazepam treatment until 24 h, but had disappeared after 15 days. In our model, neuronal activation (c-Fos immunohistochemistry) was observed 6 h after GLA exposure in the dentate gyrus, CA1, CA3, amygdala, piriform and entorhinal cortices, indicating the activation of the limbic system. In these structures, Fluoro-Jade C and Cresyl violet staining did not show neuronal suffering. However, astroglial activation was clearly observed at 24 h and 15 days after GLA treatment in the amygdala, piriform and entorhinal cortices by PCR quantitative, western blot and immunohistochemistry. Concomitantly, glutamine synthetase mRNA expression (PCR quantitative), protein expression (western blot) and enzymatic activity were upregulated. In conclusion, our study suggests that GLA-induced seizures: (a) involved limbic structures and (b) induced astrocytosis without neuronal degeneration as an evidence of a reactive astrocyte beneficial effect for neuronal protection.

Topics: Aminobutyrates; Animals; Anticonvulsants; Astrocytes; Brain; Cerebral Cortex; Diazepam; Electroencephalography; Glutamate-Ammonia Ligase; Herbicides; Hippocampus; Male; Mice; Mice, Inbred C57BL; Neurons; Organophosphates; Proto-Oncogene Proteins c-fos; Seizures

In acute glufosinate poisoning, sudden respiratory arrest and convulsion can occur after a latent period of 4-60 h. There is still no factor that accurately predicts the occurrence of these symptoms.. To elucidate the predictors of severe effects following acute glufosinate poisoning.. This study is a retrospective observational case series. The subjects were 16 patients who had acute glufosinate poisoning. They were divided into a group with respiratory arrest or convulsion during hospitalization (severe group) and a group without (non-severe group). The following characteristics (or predictors) were compared between the groups: age, sex, calculated amount of glufosinate (volume of ingested poison (glufosinate-containing herbicide) × glufosinate concentration of the product), time duration from poison ingestion to arrival at our hospital, use of gastric lavage, use of whole bowel irrigation, Glasgow Coma Scale, laboratory parameters, PaO₂/FiO₂ ratio (P/F ratio), shock index, and presence or absence of systemic inflammatory response syndrome (SIRS) on arrival.. The P/F ratio was significantly lower in the severe group than in the non-severe group (median, 287.5 vs. 409.0; P = 0.049). The receiver operating characteristic (ROC) curve was plotted for the predictor of increasing severity based on the P/F ratio. The area under the curve was 0.714, and the optimal cutoff point for increasing severity was 374.0. The sensitivity was 75.0%, specificity of 71.4%, and accuracy of 75.0%. The shock index was significantly higher (median, 0.52 vs. 0.41; P = 0.031). Significantly more patients had SIRS in the severe group than in the non-severe group (P = 0.015). Logistic regression analysis was performed with a backward elimination procedure. SIRS was selected as the independent predictor of increasing severity (odds ratio, 29.810; 95% confidence interval, 1.011-878.952; P = 0.049).. Severe effects following acute glufosinate poisoning were associated with two positive SIRS criteria. A low P/F ratio may be useful for predicting the occurrence of respiratory complications.

Topics: Adult; Aged; Aged, 80 and over; Aminobutyrates; Enzyme Inhibitors; Female; Glutamate Decarboxylase; Glutamate-Ammonia Ligase; Herbicides; Humans; Male; Middle Aged; Neurotoxicity Syndromes; Oxygen; Pulmonary Circulation; Respiratory Insufficiency; Retrospective Studies; ROC Curve; Seizures; Severity of Illness Index; Systemic Inflammatory Response Syndrome; Young Adult

Although glufosinate ammonium herbicides are considered safe when used properly, ingestion of the undiluted form can cause grave outcomes. Recently, we treated a 34-yr-old man who ingested glufosinate ammonium herbicide. In the course of treatment, the patient developed apnea, mental deterioration, and sixth cranial nerve palsy; he has since been discharged with full recovery after intensive care. This case report describes the clinical features of glufosinate intoxication with a focus on sixth cranial nerve palsy. Our observation suggests that neurologic manifestations after ingestion of a "low-grade toxicity herbicide" are variable and more complex than that was previously considered.

Topics: Abducens Nerve Diseases; Adult; Aminobutyrates; Enzyme Inhibitors; Herbicides; Humans; Male; Seizures; Surface-Active Agents; Unconsciousness

7-Nitroindazole (NI) is a widely used inhibitor of neuronal nitricoxide synthase (nNOS) used to study the role of the neuronal NO pathway in the nervous system. 7-NI prevents convulsions, including 2-amino-4-methylphosphinobutyric acid (glufosinate)-induced convulsions, in experimental models. Herein, we examined nNOS involvement in glufosinate-induced convulsions and the specificity of 7-NI for nNOS. Another nNOS inhibitor, 1-[2-(trifluoromethyl)phenyl]imidazole (TRIM), inhibited NOS activity in vivo, and it prevented glufosinate-induced convulsions. In contrast, an endothelial NOS inhibitor, N(5)-(1-iminoethyl)-l-ornithine, inhibited NOS activity in vivo, but it did not prevent the convulsions. These results suggest the involvement of nNOS in glufosinate-induced convulsions. However, a nonspecific NOS inhibitor, N(omega)-nitro-l-arginine methyl ester, inhibited NOS activity in vivo, but it failed to prevent glufosinate-induced convulsions. 6-NI and indazole, which did not inhibit NOS activity in vivo, suppressed glufosinate-induced convulsions. Moreover, glufosinate elicited convulsions in nNOS-deficient mice. These results suggest the anticonvulsant effects of 7-NI and TRIM on glufosinate-induced convulsions do not involve nNOS inhibition, instead possibly being related to an undefined property of nitrogen-containing chemical structures.

Topics: Aminobutyrates; Animals; Anticonvulsants; Brain; Herbicides; Imidazoles; Indazoles; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type I; Seizures

Phosphinothricin (PPT), the active component of a widely used herbicide, induces convulsions in rodents and humans. PPT shares structural analogy with glutamate, which could explain its powerful inhibitory effect on glutamine synthetase and its probable binding to glutamate receptors. To characterize the epileptogenic effect of PPT, electrographic and behavioural studies were carried out on PPT-treated adult mice. We investigated the role of N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) production in induction of seizures triggered by PPT, by using specific NMDA antagonist and nitric oxide synthase (NOS) inhibitor. The inhibitory effect of PPT on glutamine synthetase of mouse brain was assessed after in vitro and in vivo treatments. The results obtained show that PPT induces tonic-clonic seizures and generalized convulsions in mice. They suggest that these seizures are mediated through an NMDA receptor activation and NO production, without involvement of inhibition of glutamine synthetase.

Topics: Aminobutyrates; Animals; Brain; Dizocilpine Maleate; Electroencephalography; Enzyme Inhibitors; Epilepsy; Excitatory Amino Acid Antagonists; Glutamate-Ammonia Ligase; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Seizures

Glufosinate ammonium, a broad-spectrum herbicide, causes convulsion in rodents and humans. Because of the structural similarities between glufosinate and glutamate, the convulsion induced by glufosinate ammonium may be ascribed to glutamate receptor activation. Three N-methyl-D-asparate (NMDA) receptor antagonists, dizocilpine, LY235959, and Compound 40, and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist, NBQX, were coadministrated with glufosinate ammonium (80 mg/kg, intraperitoneally) in mice. Statistical analyses showed that the NMDA receptor antagonists markedly inhibited the convulsions, while the AMPA/kainate receptor antagonist had no effect on the convulsion. These results suggest that the convulsion caused by glufosinate ammonium is mediated through NMDA receptors.

Topics: Aminobutyrates; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Herbicides; Male; Mice; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures

Glufosinate ammonium (GLA), the active ingredient in the non-selective herbicide BASTA (18.5% GLA), is a phosphinic acid analogue of glutamic acid. We report 2 cases of GLA poisoning with late onset convulsions and increased serum CK in spite of low blood concentrations of GLA after hemodialysis. A 69-y-old female was admitted to the emergency department after taking 500 ml of BASTA. On arrival she was conscious, and gut decontamination, hemodialysis and hemoperfusion were performed. However, 8 1/2 hours after ingestion, general convulsions occurred. Her serum OK increased to a peak of 24,900 IU/L on the third day of admission. An 87-y-old male was admitted to the emergency department 3 1/2 hours after taking 200 ml of BASTA and receiving gastric lavage at a local emergency room. On arrival he was conscious, and serial activated charcoal and hemodialysis was performed. Blood concentration of GLA after hemodialysis decreased from 1.56 micrograms/ml to 0.68 micrograms/ml. Thirty hours after admission he had general convulsions. GLA was not detected in the cerebrospinal fluid 6 h after the convulsions. His serum CK increased to a peak of 17,870 IU/L on the fifth day of admission.

Topics: Aged; Aged, 80 and over; Aminobutyrates; Amylases; Creatine Kinase; Female; Hemoperfusion; Herbicides; Humans; Male; Poisoning; Renal Dialysis; Seizures; Suicide, Attempted

We report a case of a 59-y-old woman who ingested a herbicide containing glufosinate. Though suffering from severe toxicity of this herbicide, she did not develop convulsions, which experimentally occurs in rats treated with glufosinate. The mechanisms of convulsions are not clear. Several clinical findings in poisoning by this herbicide are suspected to be caused by the surfactant components.

Topics: Aminobutyrates; Charcoal; Consciousness Disorders; Diuresis; Female; Furosemide; Herbicides; Humans; Japan; Middle Aged; Poisoning; Seizures; Suicide, Attempted; Surface-Active Agents