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

Almeida, Carlos Gabriel Moreira de; 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; Lima, Maria Elena de; Silva, Carolina Nunes da; Vinadé, Lúcia; Rowan, Edward G.; Costa, Jaderson Costa da; Belo, Cháriston André Dal; Carlini, Celia Regina Ribeiro da Silva

doi:10.1016/j.tox.2021.152737

Cited by 9 publications

(7 citation statements)

References 78 publications

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“…The neurotoxicity of purified HPU administered to rats intraperitoneally was first described by Baik and colleagues in 2005 [ 65 ], who observed hypothermia, convulsion and death of the animals. It should be noted that these same effects occur in rats and mice injected with CNTX, a highly neurotoxic urease isolated from the Canavalia ensiformis plant, and these events are independent of the protein’s enzymatic activity [ 66 , 67 ]. However, these symptoms of HPU’s neurotoxicity do not allow establishing, from epidemiological data, that there is a correlation between H. pylori infection with AD tauopathy.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Urease: Potential Contributions to Alzheimer’s Disease

Uberti

Callai-Silva

Grahl

et al. 2022

IJMS

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Alzheimer’s disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in a brain with AD. A filtrate of Helicobacter pylori’s culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood–brain barrier and directly induce tau’s phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here, the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed to HPU (50–300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1β and TNF-α, and showed reduced viability. Rats received daily i.p., HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Ser199, Thr205 and Ser396 sites, with no alterations in total tau or GSK-3β levels, and overexpression of Iba1, a marker of microglial activation, were seen in hippocampal homogenates. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Urease: Potential Contributions to Alzheimer’s Disease

Uberti

Callai-Silva

Grahl

et al. 2022

IJMS

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“…Administration of ureases to rodents can cause several systemic effects, such as bradycardia, hypoglycemia, hypothermia, hypoxia, and seizures, that eventually precede death [ 1 , 55 ]. Here, we aimed to evaluate the acute (within 24 h) in vivo effects triggered by systemic (e.v.)…”

Section: Resultsmentioning

confidence: 99%

“…Other symptoms induced by canatoxin include bradycardia, hypotension, hypothermia, hypoxia, and biphasic alterations of glycemia [ 48 , 57 , 113 ]. Studies involving canatoxin and JBU in rodents revealed an electroencephalographic pattern and brain imaging consistent with a seizure-inducing effect and alterations in synaptic plasticity, with persistent long-term depression in the hippocampus [ 55 ]. In vitro, C. ensiformis ureases induced L-glutamate release, raised the intracellular levels of calcium, and increased the rate of spontaneous firing of neurons [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies involving canatoxin and JBU in rodents revealed an electroencephalographic pattern and brain imaging consistent with a seizure-inducing effect and alterations in synaptic plasticity, with persistent long-term depression in the hippocampus [ 55 ]. In vitro, C. ensiformis ureases induced L-glutamate release, raised the intracellular levels of calcium, and increased the rate of spontaneous firing of neurons [ 55 ]. Canatoxin did not affect the voltage-gated Na + , K + , or Ca 2+ currents, nor did it interfere with the cholinergic receptors [ 55 ], suggesting an indirect mode of action possibly related to membrane-disturbing properties [ 114 , 115 ].…”

Section: Discussionmentioning

confidence: 99%

“…Following these findings, our group has described the non-ureolytic effects of ureases from different sources, including the bacterial ureases from Sporosarcina pasteurii , H. pylori (reviewed in [ 1 , 2 ]) and P. mirabilis [ 13 , 50 ]. Among these enzyme-independent effects of ureases are platelet aggregation [ 44 , 51 , 52 ], chemotaxis induction [ 45 , 53 ], exocytosis [ 44 , 54 ], production of reactive oxygen species [ 13 , 45 ], neurotransmitter release [ 54 , 55 ], production of pro-inflammatory cytokines [ 13 , 43 , 46 , 47 ] and changes in Ca 2+ transport [ 13 , 46 , 52 , 54 ]. In the case of P. mirabilis urease (PMU), the pro-inflammatory effects in cultured cells observed for the holourease (αβγ) 3 were not associated with an increase in the ammonia levels in the medium, discarding the contribution of the enzyme activity [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Could the Urease of the Gut Bacterium Proteus mirabilis Play a Role in the Altered Gut–Brain Talk Associated with Parkinson’s Disease?

Grahl,

Andrade,

Perin

et al. 2023

Microorganisms

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Intestinal dysbiosis seems to play a role in neurodegenerative pathologies. Parkinson’s disease (PD) patients have an altered gut microbiota. Moreover, mice treated orally with the gut microbe Proteus mirabilis developed Parkinson’s-like symptoms. Here, the possible involvement of P. mirabilis urease (PMU) and its B subunit (PmUreβ) in the pathogenesis of PD was assessed. Purified proteins were given to mice intraperitoneally (20 μg/animal/day) for one week. Behavioral tests were conducted, and brain homogenates of the treated animals were subjected to immunoassays. After treatment with PMU, the levels of TNF-α and IL-1β were measured in Caco2 cells and cellular permeability was assayed in Hek 293. The proteins were incubated in vitro with α-synuclein and examined via transmission electron microscopy. Our results showed that PMU treatment induced depressive-like behavior in mice. No motor deficits were observed. The brain homogenates had an increased content of caspase-9, while the levels of α-synuclein and tyrosine hydroxylase decreased. PMU increased the pro-inflammatory cytokines and altered the cellular permeability in cultured cells. The urease, but not the PmUreβ, altered the morphology of α-synuclein aggregates in vitro, forming fragmented aggregates. We concluded that PMU promotes pro-inflammatory effects in cultured cells. In vivo, PMU induces neuroinflammation and a depressive-like phenotype compatible with the first stages of PD development.

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