The Phoneutria nigriventer spider toxin, PnTx4-5-5, promotes neuronal survival by blocking NMDA receptors

Silva, Flávia Rodrigues da; Batista, Edleusa Marques; Gomez, Marcus V.; Kushmerick, Christopher; Silva, Juliana F. Da; Cordeiro, Marta N.; Vieira, Luciene Bruno; Ribeiro, Fabíola M.

doi:10.1016/j.toxicon.2016.01.056

Cited by 20 publications

(16 citation statements)

References 38 publications

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“…However, in order to investigate if the antinociceptive effect of these insect-toxins involves the inhibition of sodium channels, other assays are required, including the test of its effects on Na v s 1.7, 1.8 and 1.9, which are critically involved in pain mechanisms. Another possible target of these toxins, as observed for rΓ-ctenitoxin-Pn1a [ 38 , 39 ] is the NMDA receptor, which could also be involved in the observed antinociceptive effects. Other studies are in progress to try to clarify this point.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we demonstrated that this toxin causes antinociception when peripherally injected in rats [ 38 ]. Additionally, it was recently shown that Γ-ctenitoxin-Pn1a promotes neuroprotection under insults of high levels of glutamate, in primary-cultured corticostriatal neurons from wild type mice, as well as from a mouse model of Huntington's disease [ 39 ]. It is well known that NMDA receptors are involved in nociception and that NMDA antagonists can produce antinociception [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

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δ-Ctenitoxin-Pn1a, a Peptide from Phoneutria nigriventer Spider Venom, Shows Antinociceptive Effect Involving Opioid and Cannabinoid Systems, in Rats

Emerich

Ferreira

Cordeiro

et al. 2016

Toxins

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PnTx4(6-1), henceforth renamed δ-Ctenitoxin-Pn1a (δ-CNTX-Pn1a), a peptide from Phoneutria nigriventer spider venom, initially described as an insect toxin, binds to site 3 of sodium channels in nerve cord synaptosomes and slows down sodium current inactivation in isolated axons in cockroaches (Periplaneta americana). δ-CNTX-Pn1a does not cause any apparent toxicity to mice, when intracerebroventricularly injected (30 μg). In this study, we evaluated the antinociceptive effect of δ-CNTX-Pn1a in three animal pain models and investigated its mechanism of action in acute pain. In the inflammatory pain model, induced by carrageenan, δ-CNTX-Pn1a restored the nociceptive threshold of rats, when intraplantarly injected, 2 h and 30 min after carrageenan administration. Concerning the neuropathic pain model, δ-CNTX-Pn1a, when intrathecally administered, reversed the hyperalgesia evoked by sciatic nerve constriction. In the acute pain model, induced by prostaglandin E2, intrathecal administration of δ-CNTX-Pn1a caused a dose-dependent antinociceptive effect. Using antagonists of the receptors, we showed that the antinociceptive effect of δ-CNTX-Pn1a involves both the cannabinoid system, through CB1 receptors, and the opioid system, through μ and δ receptors. Our data show, for the first time, that δ-Ctenitoxin-Pn1a is able to induce antinociception in inflammatory, neuropathic and acute pain models.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

δ-Ctenitoxin-Pn1a, a Peptide from Phoneutria nigriventer Spider Venom, Shows Antinociceptive Effect Involving Opioid and Cannabinoid Systems, in Rats

Emerich

Ferreira

Cordeiro

et al. 2016

Toxins

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“…In this study, the Cav-1 immunoreactivity of pyramidal neurons of CA hippocampal subfields is documental for the role of the protein also in neuronal cells function; PNV seemed to enhance the protein labeling (compare the intensity of Cav-1 labeling of pyramidal neurons pictured in Figure 3C (control) and Figure 3D (PNV-treated)). In hippocampal neurons, there is indication that induction of Cav-1 is triggered through glutamate exposure, apparently through kainate and AMPA-type receptors [50], receptors that are involved in hypernociception caused by PNV [6,7,51,52]. …”

Section: Discussionmentioning

confidence: 99%

Age-Related Modulations of AQP4 and Caveolin-1 in the Hippocampus Predispose the Toxic Effect of Phoneutria nigriventer Spider Venom

Soares

Stávale

Mendonça

et al. 2016

IJMS

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We have previously demonstrated that Phoneutria nigriventer venom (PNV) causes blood–brain barrier (BBB) breakdown, swelling of astrocytes end-feet and fluid permeation into brain interstitium in rats. Caveolae and water channels respond to BBB alterations by co-participation in shear stress response and edema formation/resolution. Herein, we showed post-natal developmental-related changes of two BBB-associated transporter proteins: the endothelial caveolin-1 (Cav-1), the major scaffolding protein from caveolae frame, and the astroglial aquaporin-4 (AQP4), the main water channel protein expressed in astrocytic peri-vascular end-feet processes, in the hippocampus of rats intraperitoneally-administered PNV. Western blotting protein levels; immunohistochemistry (IHC) protein distribution in CA1, CA2, and CA3 subfields; and gene expression by Real Time-Polymerase Chain Reaction (qPCR) were assessed in post-natal Day 14 (P14) and 8–10-week-old rats over critical periods of envenomation. The intensity and duration of the toxic manifestations indicate P14 neonate rats more vulnerable to PNV than adults. Histologically, the capillaries of P14 and 8–10-week-old rats treated with PNV showed perivascular edema, while controls did not. The intensity of the toxic manifestations in P14 decreases temporally (2 > 5 > 24 h), while inversely the expression of AQP4 and Cav-1 peaked at 24 h when clinically PNV-treated animals do not differ from saline controls. IHC of AQP4 revealed that hippocampal CA1 showed the least expression at 2 h when toxic manifestation was maximal. Subfield IHC quantification revealed that in P14 rats Cav-1 peaked at 24 h when toxic manifestations were absent, whereas in 8–10-week-old rats Cav-1 peaked at 2 h when toxic signs were highest, and progressively attenuated such increases until 24 h, remaining though significantly above baseline. Considering astrocyte-endothelial physical and functional interactions, we hypothesize that age-related modulations of AQP4 and Cav-1 might be linked both to changes in functional properties of astrocytes during post-natal development and in the BBB breakdown induced by the venom of P. nigriventer.

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“…Glutamate excitotoxicity is regarded as an important cell death trigger not only in AD, but also in other neurodegenerative diseases such as HD. Corroborating the hypothesis that Phoneutria nigriventer toxins are also valid therapeutic options to treat HD, PhTx4-5-5 was shown to protect corticostriatal neuronal cultures obtained from a mouse model of HD, the BACHD mice ( Silva et al, 2016 ).…”

Section: Animal Toxins To Treat Neurodegenerative Diseasesmentioning

confidence: 98%

“…Further studies will be important to demonstrate whether PhKv anti-AChE activity could be beneficial in AD. Another Phoneutria toxin, PhTx4-5-5, showed neuroprotective activity against Aβ and glutamate-induced excitotoxicity by blockage of NMDA receptors in mice corticostriatal neuronal cultures ( Figure 1 ) ( Silva et al, 2016 ). Glutamate excitotoxicity is regarded as an important cell death trigger not only in AD, but also in other neurodegenerative diseases such as HD.…”

Section: Animal Toxins To Treat Neurodegenerative Diseasesmentioning

confidence: 99%

Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases

et al. 2018

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Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death. Venoms are fruitful natural sources of new molecules, which have been relentlessly enhanced by evolution through natural selection. Several studies indicate that venom components can exhibit selectivity and affinity for a wide variety of targets in mammalian systems. For instance, an expressive number of natural peptides identified in venoms from animals, such as snakes, scorpions, bees, and spiders, were shown to lessen inflammation, regulate glutamate release, modify neurotransmitter levels, block ion channel activation, decrease the number of protein aggregates, and increase the levels of neuroprotective factors. Thus, these venom components hold potential as therapeutic tools to slow or even halt neurodegeneration. However, there are many technological issues to overcome, as venom peptides are hard to obtain and characterize and the amount obtained from natural sources is insufficient to perform all the necessary experiments and tests. Fortunately, technological improvements regarding heterologous protein expression, as well as peptide chemical synthesis will help to provide enough quantities and allow chemical and pharmacological enhancements of these natural occurring compounds. Thus, the main focus of this review is to highlight the most promising studies evaluating animal toxins as therapeutic tools to treat a wide variety of neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, brain ischemia, glaucoma, amyotrophic lateral sclerosis, and multiple sclerosis.

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The Phoneutria nigriventer spider toxin, PnTx4-5-5, promotes neuronal survival by blocking NMDA receptors

Cited by 20 publications

References 38 publications

δ-Ctenitoxin-Pn1a, a Peptide from Phoneutria nigriventer Spider Venom, Shows Antinociceptive Effect Involving Opioid and Cannabinoid Systems, in Rats

δ-Ctenitoxin-Pn1a, a Peptide from Phoneutria nigriventer Spider Venom, Shows Antinociceptive Effect Involving Opioid and Cannabinoid Systems, in Rats

Age-Related Modulations of AQP4 and Caveolin-1 in the Hippocampus Predispose the Toxic Effect of Phoneutria nigriventer Spider Venom

Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases

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