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

Almeida, Carlos Gabriel Moreira and Costa-Higuchi, Kiyo and Piovesan, Angela Regina and Moro, Carlo Frederico and Venturin, Gianina Teribele and Greggio, Samuel and Costa-Ferro, Zaquer Susana and Salamoni, Simone Denise and Peigneur, Steve and Tytgat, Jan and de Lima, Maria Elena and Silva, Carolina Nunes da and Vinadé, Lúcia and Rowan, Edward G. and DaCosta, Jaderson Costa and Dal Belo, Cháriston André and Carlini, Celia Regina (2021) Neurotoxic and convulsant effects induced by jack bean ureases on the mammalian nervous system. Toxicology, 454. 152737. ISSN 0300-483X

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    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 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.