Analgesic Effects of Huwentoxin-IV on Animal Models of Inflammatory and Neuropathic Pain

Liu, Yu; Wu, Zhe; Tang, Dongfang; Xun, Xiaohong; Liu, Lichao; Li, Xianlei; Nie, Dongsong; Xiang, Yang; Yi, Jianming; Yi, Jizu

doi:10.2174/09298665113206660119

Cited by 31 publications

(25 citation statements)

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“…Various analgesic toxins have been proposed as candidates to replace opioids, because of their well-known side-effects. Hence, HwTx-IV, HnTx-IV, Pn3a and ProTx-II were shown to decrease pain at the level of morphine relief, in a dose-depending manner, in neuropathic (mainly spared nerve injury and diabetic neuropathy) and all inflammatory pain models, revealing a real evidence of their analgesic potential as drugs ( Liu et al, 2014a , b , Tanaka et al, 2015 ; Deuis et al, 2017a ; Flinspach et al, 2017 ). Pn3a and the ProTx-II mutant JNJ63955918 were also described as being effective on acute thermal pain tests ( Deuis et al, 2017a ; Flinspach et al, 2017 ).…”

Section: Analgesic Spider Toxins Targeting the Na V mentioning

confidence: 94%

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

et al. 2018

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Although necessary for human survival, pain may sometimes become pathologic if long-lasting and associated with alterations in its signaling pathway. Opioid painkillers are officially used to treat moderate to severe, and even mild, pain. However, the consequent strong and not so rare complications that occur, including addiction and overdose, combined with pain management costs, remain an important societal and economic concern. In this context, animal venom toxins represent an original source of antinociceptive peptides that mainly target ion channels (such as ASICs as well as TRP, CaV, KV and NaV channels) involved in pain transmission. The present review aims to highlight the NaV1.7 channel subtype as an antinociceptive target for spider toxins in adult dorsal root ganglia neurons. It will detail (i) the characteristics of these primary sensory neurons, the first ones in contact with pain stimulus and conveying the nociceptive message, (ii) the electrophysiological properties of the different NaV channel subtypes expressed in these neurons, with a particular attention on the NaV1.7 subtype, an antinociceptive target of choice that has been validated by human genetic evidence, and (iii) the features of spider venom toxins, shaped of inhibitory cysteine knot motif, that present high affinity for the NaV1.7 subtype associated with evidenced analgesic efficacy in animal models.

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Section: Analgesic Spider Toxins Targeting the Na V mentioning

confidence: 94%

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

et al. 2018

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“…The in vivo activity of HwTx-IV was previously reported in rat models of formalin-induced pain and spared nerve injury, where it blocked pain behaviours at doses between 25 and 200 μg/kg [41]. This exquisite in vivo potency may at least in part be due to the strain of animals used, as morphine also was effective at doses at least 20 times lower than those usually required to achieve analgesia in the same models [42–45].…”

Section: Discussionmentioning

confidence: 99%

The structure, dynamics and selectivity profile of a NaV1.7 potency-optimised huwentoxin-IV variant

et al. 2017

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Venom-derived peptides have attracted much attention as potential lead molecules for pharmaceutical development. A well-known example is Huwentoxin-IV (HwTx-IV), a peptide toxin isolated from the venom of the Chinese bird-eating spider Haplopelma schmitdi. HwTx-IV was identified as a potent blocker of a human voltage-gated sodium channel (hNaV1.7), which is a genetically validated analgesic target. The peptide was promising as it showed high potency at NaV1.7 (IC50 ~26 nM) and selectivity over the cardiac NaV subtype (NaV1.5). Mutagenesis studies aimed at optimising the potency of the peptide resulted in the development of a triple-mutant of HwTx-IV (E1G, E4G, Y33W, m3-HwTx-IV) with significantly increased potency against hNaV1.7 (IC50 = 0.4 ± 0.1 nM) without increased potency against hNaV1.5. The activity of m3-HwTx-IV against other NaV subtypes was, however, not investigated. Similarly, the structure of the mutant peptide was not characterised, limiting the interpretation of the observed increase in potency. In this study we produced isotope-labelled recombinant m3-HwTx-IV in E. coli, which enabled us to characterise the atomic-resolution structure and dynamics of the peptide by NMR spectroscopy. The results show that the structure of the peptide is not perturbed by the mutations, whilst the relaxation studies reveal that residues in the active site of the peptide undergo conformational exchange. Additionally, the NaV subtype selectivity of the recombinant peptide was characterised, revealing potent inhibition of neuronal NaV subtypes 1.1, 1.2, 1.3, 1.6 and 1.7. In parallel to the in vitro studies, we investigated NaV1.7 target engagement of the peptide in vivo using a rodent pain model, where m3-HwTx-IV dose-dependently suppressed spontaneous pain induced by the NaV1.7 activator OD1. Thus, our results provide further insight into the structure and dynamics of this class of peptides that may prove useful in guiding the development of inhibitors with improved selectivity for analgesic NaV subtypes.

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“…For example, μ-TRTX-Hhn1b, isolated from the venom of Ornithoctonus hainana , and huwentoxin-IV, isolated from the venom of Ornithoctonus huwena , are Nav1.7 channel inhibitors that efficiently alleviate acute inflammatory pain and chronic neuropathic pain in animals [30, 31]. Mechanotoxin 4, isolated from Grammostola rosea venom, reduces mechanical and neuropathic pain by blocking stretch-activated cation channels [32].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterization of venoms from three theraphosid spiders: Poecilotheria regalis, Ceratogyrus darlingi and Brachypelma epicureanum

García-Arredondo¹,

Rodríguez-Rios²,

Díaz-Peña³

et al. 2015

J Venom Anim Toxins Incl Trop Dis

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BackgroundTarantulas (Theraphosidae) represent an important source of novel biologically active compounds that target a variety of ion channels and cell receptors in both insects and mammals. In this study, we evaluate and compare the pharmacological activity of venoms from three taxonomically different theraphosid spiders bred in captivity: Poecilotheria regalis, an aggressive arboreal tarantula from southeastern India; Ceratogyrus darlingi, an aggressive tarantula from southern Africa; and Brachypelma epicureanum, a docile tarantula from the Yucatan dry forest of Mexico. Prior to this study, no research had been conducted with regard to the composition and pharmacological activity of these venoms.MethodsThe pharmacological characterization of the venoms was described for the first time by the assessment of their toxicity in crickets (LD50) along with their nociceptive (by using the formalin test), hyaluronidase, phospholipase A2, edematogenic and caseinolytic activity.ResultsP. regalis and B. epicureanum venoms induced a similar lethal effect on crickets (LD50 = 5.23 ± 3.1 and 14.4 ± 5.0 μg protein/g 48 h post-injection, respectively), whereas C. darlingi venom (119.4 ± 29.5 μg protein/g 48 h post-injection) was significantly less lethal than the other two venoms. All three venoms induced similar edematogenic activity on rats but did not induce nociceptive behavior. The assessment of enzymatic activity indicated that P. regalis venom induces significantly higher hyaluronidase activity (27.6 ± 0.9 TRU/mg) than both C. darlingi (99.7 ± 1.9 TRU/mg) and B. epicureanum (99.6 ± 1.6 TRU/mg); these latter venoms did not display phospholipase A2 or caseinolytic activity.ConclusionsThis study demonstrates that these theraphosid spiders of different habitats produce venoms with different activities. P. regalis venom displays a high level of hyaluronidase activity, which may be associated with its potentially medically significant bite.

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Analgesic Effects of Huwentoxin-IV on Animal Models of Inflammatory and Neuropathic Pain

Cited by 31 publications

References 0 publications

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

The structure, dynamics and selectivity profile of a NaV1.7 potency-optimised huwentoxin-IV variant

Pharmacological characterization of venoms from three theraphosid spiders: Poecilotheria regalis, Ceratogyrus darlingi and Brachypelma epicureanum

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