Abstract
The demonstration that carbon monoxide releasing molecules (CORMs) affect experimental systems by the release of carbon monoxide, and not via the interaction of the inactivated CORM, has been an accepted paradigm for decades. However, it has recently been documented that a radical intermediate formed during carbon monoxide release from ruthenium (Ru)-based CORM (CORM-2) interacts with histidine and can inactivate bee phospholipase A2 activity. Using a thrombelastographic based paradigm to assess procoagulant activity in human plasma, this study tested the hypothesis that a Ru-based radical and not carbon monoxide was responsible for CORM-2 mediated inhibition of Atheris, Echis, and Pseudonaja species snake venoms. Assessment of the inhibitory effects of ruthenium chloride (RuCl3) on snake venom activity was also determined. CORM-2 mediated inhibition of the three venoms was found to be independent of carbon monoxide release, as the presence of histidine-rich albumin abrogated CORM-2 inhibition. Exposure to RuCl3 had little effect on Atheris venom activity, but Echis and Pseudonaja venom had procoagulant activity significantly reduced. In conclusion, a Ru-based radical and ion inhibited procoagulant snake venoms, not carbon monoxide. These data continue to add to our mechanistic understanding of how Ru-based molecules can modulate hemotoxic venoms, and these results can serve as a rationale to focus on perhaps other, complementary compounds containing Ru as antivenom agents in vitro and, ultimately, in vivo.
Highlights
The use of carbon monoxide releasing molecules (CORMs) to deliver carbon monoxide (CO) in a site-directed fashion to presumably alter heme-modulated systems has been part of experimental designs for decades, with hundreds of manuscripts incorporating this methodology
The key element of the paradigm that implicates CO as the mechanism behind the effects of CORMs is the determination that the inactivated releasing molecule, the portion of the CORM that remains after CO release, has no effect or a different effect on the system tested with the CORM compared to the anticipated CO effect
This laboratory has used this CORM-based paradigm for the past few years to demonstrate that CO inhibited the various procoagulant and anticoagulant activities of hemotoxic venoms and enzymes collected from dozens of snake and lizard species [1,2,3,4,5,6,7,8,9,10,11,12,13]
Summary
The use of carbon monoxide releasing molecules (CORMs) to deliver carbon monoxide (CO) in a site-directed fashion to presumably alter heme-modulated systems has been part of experimental designs for decades, with hundreds of manuscripts incorporating this methodology. It was entirely possible that Ru-based interactions with venom proteins could be responsible for the inhibition noted in our previous works [13]; and critically, if Ru-based modifications were the underpinning of such inhibition rather than the interaction of CO with a heme group, Ru-based CORMs could well serve as permeant antivenom agents The importance of these line of investigation involving ion channels [14], phospholipase A2 [15], and metalloproteinases [16] is that they lay the foundation to seriously reconsider the paradigm that Ru-based CORMs affect systems as simple as enzymes to as complex as whole animal models of disease in CO-independent ways—potentially affecting the interpretation of data contained in several hundred manuscripts. Sinci.p2r0o19c,o2a0g, xulFaOnRt PaEctEiRviRtEyVwIEeWre assessed with human plasma via changes in coagulation kin eotfi1c2s determined with thrombelastography
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
