Neurotoxic and convulsant effects induced by jack bean ureases on the mammalian nervous system

• Published in: Toxicology (Amsterdam) Vol. 454; p. 152737
• Main Authors: Almeida, Carlos Gabriel Moreira, Costa-Higuchi, Kiyo, Piovesan, Angela Regina, Moro, Carlo Frederico, Venturin, Gianina Teribele, Greggio, Samuel, Costa-Ferro, Zaquer Susana, Salamoni, Simone Denise, Peigneur, Steve, Tytgat, Jan, de Lima, Maria Elena, Silva, Carolina Nunes da, Vinadé, Lúcia, Rowan, Edward G., DaCosta, Jaderson Costa, Dal Belo, Cháriston André, Carlini, Celia Regina
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 30.04.2021
• Subjects: Animals; Canatoxin; Canavalia - chemistry; Convulsants - isolation & purification; Convulsants - toxicity; Epileptogenesis; Female; Ion channels; L-glutamate; Long term potentiation; Male; Mice; Nervous System - drug effects; Nervous System - pathology; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - physiopathology; Plant Proteins - isolation & purification; Plant Proteins - toxicity; Positron emission tomography; Rats; Rats, Wistar; Toxins, Biological - isolation & purification; Toxins, Biological - toxicity; Urease - isolation & purification; Urease - toxicity; Xenopus laevis; CNTX; Epileptogenesis; microPET; Canatoxin; Long term potentiation; LTP; Ion channels; L-glutamate; JBU; Positron emission tomography
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2021.152737

•Jack bean ureases, JBU and canatoxin (CNTX), cause seizures in rodents.•Electrophysiology and brain imaging were applied to study their mode of action.•Ureases’ neurotoxicity is indirect and possibly due to membrane-disturbing effects.•Ureases may have a role in microbial diseases affecting the central nervous system. Ureases are microbial virulence factors either because of the enzymatic release of ammonia or due to many other non-enzymatic effects. Here we studied two neurotoxic urease isoforms, Canatoxin (CNTX) and Jack Bean Urease (JBU), produced by the plant Canavalia ensiformis, whose mechanisms of action remain elusive. The neurotoxins provoke convulsions in rodents (LD50 ∼2 mg/kg) and stimulate exocytosis in cell models, affecting intracellular calcium levels. Here, electrophysiological and brain imaging techniques were applied to elucidate their mode of action. While systemic administration of the toxins causes tonic-clonic seizures in rodents, JBU injected into rat hippocampus induced spike-wave discharges similar to absence-like seizures. JBU reduced the amplitude of compound action potential from mouse sciatic nerve in a tetrodotoxin-insensitive manner. Hippocampal slices from CNTX-injected animals or slices treated in vitro with JBU failed to induce long term potentiation upon tetanic stimulation. Rat cortical synaptosomes treated with JBU released L-glutamate. JBU increased the intracellular calcium levels and spontaneous firing rate in rat hippocampus neurons. MicroPET scans of CNTX-injected rats revealed increased [18]Fluoro-deoxyglucose uptake in epileptogenesis-related areas like hippocampus and thalamus. Curiously, CNTX did not affect voltage-gated sodium, calcium or potassium channels currents, neither did it interfere on cholinergic receptors, suggesting an indirect mode of action that could be related to the ureases’ membrane-disturbing properties. Understanding the neurotoxic mode of action of C. ensiformis ureases could help to unveil the so far underappreciated relevance of these toxins in diseases caused by urease-producing microorganisms, in which the human central nervous system is affected.