Anticoagulant activity of krait, coral snake, and cobra neurotoxic venoms with diverse proteomes are inhibited by carbon monoxide

Nielsen, Vance G.; Frank, Nathaniel; Turchioe, Brian J.

doi:10.1097/mbc.0000000000000842

Cited by 5 publications

(21 citation statements)

References 29 publications

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“…Dendroaspis polylepis [13,14] 31.0-45.1 48.9-61.1 1.8-3.2 Dendroaspis angusticeps [13,15] 69.2-71. 4 14.5-16. 3 3.4-6.7 Dendroaspis jamesoni [13] 80.…”

Section: -Ftx (%) Kunitz-type Spi (%) Metalloproteinase (%)mentioning

confidence: 99%

“…Fourth, the contribution of a putative ruthenium (Ru) radical formed during the release of carbon monoxide from CORM-2 towards the inhibition of venom anticoagulant activity was performed as previously described [18]. Such determinations of the mechanism responsible for the CORM-2-mediated inhibition of snake venom hemotoxicity is of interest considering its in vitro efficacy against numerous species' venoms or isolated venom enzymes, as previously noted [4][5][6][7]19].…”

Section: -Ftx (%) Kunitz-type Spi (%) Metalloproteinase (%)mentioning

confidence: 99%

“…This is the case as the venom solution used is a 1% addition to the plasma mix used in our thrombelastographic system [4][5][6][7]19]. The thrombelastographic paradigm used was performance-based, with the criteria that qualifies a venom concentration to be used in experimentation, such that there were no samples with coagulation parameter values within a normal range, and that the suppression of coagulation be at least 50% of normal parameter values [4][5][6][7]19]. The initial concentrations used (n = 2-4 per concentration) were 0, 100, 200 and 500 µg/mL.…”

Section: Assessment Of the Anticoagulant Activity Of Dendroaspis Polymentioning

confidence: 99%

“…While the coagulopathic effects of hemotoxic venoms derived from venomous snakes have been of great scientific interest for several decades [1], it is only recently that investigation has intensified on the effects of neurotoxic venoms on coagulation [2][3][4][5][6][7]. Specifically, utilizing the thrombelastograph, the effects of neurotoxic venoms containing proteolytic and lipolytic enzymes on human plasma-based coagulation or isolated human thrombin-fibrinogen systems have been defined in venoms obtained from snakes within the Elapidae and Viperidae families [2][3][4][5][6][7]. Of interest, the venoms containing neurotoxic phospholipase A 2 (PLA 2 ) that were investigated were found to have their anticoagulant effects inhibited by either specific phospholipase A 2 inhibitors or tricarbonyldichlororuthenium (II) dimer (CORM-2) [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, utilizing the thrombelastograph, the effects of neurotoxic venoms containing proteolytic and lipolytic enzymes on human plasma-based coagulation or isolated human thrombin-fibrinogen systems have been defined in venoms obtained from snakes within the Elapidae and Viperidae families [2][3][4][5][6][7]. Of interest, the venoms containing neurotoxic phospholipase A 2 (PLA 2 ) that were investigated were found to have their anticoagulant effects inhibited by either specific phospholipase A 2 inhibitors or tricarbonyldichlororuthenium (II) dimer (CORM-2) [3][4][5][6][7]. Critically, these preliminary investigations exploited the ability to assess Table 1.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms Responsible for the Anticoagulant Properties of Neurotoxic Dendroaspis Venoms: A Viscoelastic Analysis

Nielsen

Wagner

Frank

2020

IJMS

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Using thrombelastography to gain mechanistic insights, recent investigations have identified enzymes and compounds in Naja and Crotalus species' neurotoxic venoms that are anticoagulant in nature. The neurotoxic venoms of the four extant species of Dendroaspis (the Black and green mambas) were noted to be anticoagulant in nature in human blood, but the mechanisms underlying these observations have never been explored. The venom proteomes of these venoms are unique, primarily composed of three finger toxins (3-FTx), Kunitz-type serine protease inhibitors (Kunitz-type SPI) and <7% metalloproteinases. The anticoagulant potency of the four mamba venoms available were determined in human plasma via thrombelastography; vulnerability to inhibition of anticoagulant activity to ethylenediaminetetraacetic acid (EDTA) was assessed, and inhibition of anticoagulant activity after exposure to a ruthenium (Ru)-based carbon monoxide releasing molecule (CORM-2) was quantified. Black mamba venom was the least potent by more than two orders of magnitude compared to the green mamba venoms tested; further, Black Mamba venom anticoagulant activity was not inhibited by either EDTA or CORM-2. In contrast, the anticoagulant activities of the green mamba venoms were all inhibited by EDTA to a greater or lesser extent, and all had anticoagulation inhibited with CORM-2. Critically, CORM-2-mediated inhibition was independent of carbon monoxide release, but was dependent on a putative Ru-based species formed from CORM-2. In conclusion, there was great species-specific variation in potency and mechanism(s) responsible for the anticoagulant activity of Dendroaspis venom, with perhaps all three protein classes-3-FTx, Kunitz-type SPI and metalloproteinases-playing a role in the venoms characterized. changes in the hemostatic effects of enzyme-based neurotoxins in response to inhibitor exposure. Thus, the use of thrombelastography to detect neurotoxin activity via biochemical substrate nexuses of plasmatic coagulation with neurochemistry was conceived.Although the anticoagulant properties of the neurotoxic venoms of several of Naja [2-6] and one Crotalus [7] species have been studied, another genus, Dendroaspis (the mambas), that kill their prey and humans with neurotoxic venom [8][9][10], were found to possess venom that was anticoagulant in vitro over 50 years ago [11,12]. Using the clotting-based, antiquated technology that was available in the 1960s, these investigators proposed that thrombin generation was impaired, fibrinogen was digested, fibrinolysis was impaired, and platelet aggregation decreased in blood exposed to Black Mamba (Dendroaspis polylepis), Eastern Green Mamba (Dendroaspis angusticeps) or Jameson's Green Mamba (Dendroaspis jamesoni) venom [11,12]. The fourth extant species, Hallowell's Green Mamba (Dendroaspis viridis), was not investigated [11,12]. Of interest, the venom of D. polylepis appeared to be between one and two orders of magnitude less potent as an anticoagulant compared to the other two species tested [11,12]. Cri...

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“…Dendroaspis polylepis [13,14] 31.0-45.1 48.9-61.1 1.8-3.2 Dendroaspis angusticeps [13,15] 69.2-71. 4 14.5-16. 3 3.4-6.7 Dendroaspis jamesoni [13] 80.…”

Section: -Ftx (%) Kunitz-type Spi (%) Metalloproteinase (%)mentioning

confidence: 99%