Neurotoxic and convulsant effects induced by jack bean ureases on the mammalian 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.
['Almeida|Carlos Gabriel Moreira|CGM|', 'Costa-Higuchi|Kiyo|K|', 'Piovesan|Angela Regina|AR|', 'Moro|Carlo Frederico|CF|', 'Venturin|Gianina Teribele|GT|', 'Greggio|Samuel|S|', 'Costa-Ferro|Zaquer Susana|ZS|', 'Salamoni|Simone Denise|SD|', 'Peigneur|Steve|S|', 'Tytgat|Jan|J|', 'de Lima|Maria Elena|ME|', 'Silva|Carolina Nunes da|CND|', 'Vinadé|Lúcia|L|', 'Rowan|Edward G|EG|', 'DaCosta|Jaderson Costa|JC|', 'Dal Belo|Cháriston André|CA|', 'Carlini|Celia Regina|CR|']
D000818:Animals D032449:Canavalia D003292:Convulsants D005260:Female D008297:Male D051379:Mice D009420:Nervous System D020258:Neurotoxicity Syndromes D010940:Plant Proteins D051381:Rats D017208:Rats, Wistar D014118:Toxins, Biological D014510:Urease D014982:Xenopus laevis
Canatoxin Long term potentiation L-glutamate Epileptogenesis Ion channels Positron emission tomography