Abstract
Naja atra envenomation is one of the most significant clinical snakebite concerns in Taiwan. Taiwanese freeze-dried neurotoxic antivenom (FNAV) is currently used clinically for the treatment of cobra snakebite, and has been shown to limit the mortality of cobra envenomation to less than 1%. However, more than half of victims (60%) require surgery because of local tissue necrosis, a major problem in patients with cobra envenomation. Although the importance of evaluating the neutralizing effect of FNAV on this pathology is recognized, whether FNAV is able to prevent the local necrosis extension induced by N. atra venom has not been investigated in detail. Cytotoxins (CTXs) are considered as the major components of N. atra venom that cause necrosis. In the current study, we isolated CTXs from whole cobra venom and used both whole venom and purified CTXs to develop animal models for assessing the neutralization potential of FNAV against venom necrotizing activity. Local necrotic lesions were successfully produced in mice using CTXs in place of whole N. atra venom. FNAV was able to rescue mice from a subcutaneously injected lethal dose of cobra venom; however, it was unable to prevent CTX-induced dermo-necrosis. Furthermore, using the minimal necrosis dose (MND) of CTXs and venom proteome data, we found a dose of whole N. atra venom suitable for FNAV and developed a workable protocol for inducing local necrosis in rodent models that successfully imitated the clinical circumstance of cobra envenoming. This information provides a more comprehensive understanding of the pathophysiology of N. atra envenomation, and serves as a guide for improving current antivenom strategies and advancing clinical snakebite management in Taiwan.
Highlights
Envenomation by snakebite is a significant global public health issue, but is a important issue in tropical countries and some poor rural communities [1]
Whether the Taiwanese freeze-dried neurotoxic antivenom (FNAV) currently in clinical use is able to prevent the local necrosis extension induced by N. atra venom is still unclear
We developed a dermo-necrosis animal model using purified cytotoxins (CTXs), the major necrosis-related proteins from N. atra venom
Summary
Envenomation by snakebite is a significant global public health issue, but is a important issue in tropical (subtropical) countries and some poor rural communities [1]. Taiwan (formerly known as Formosa) is a subtropical island located in East Asia that is home to more than 40 snake species [5], six of which are of highly venomous [6]. According to the World Health Organization (WHO) categorizations in the guideline for antivenom production, four of these venomous snakes—Bungarus multicinctus, Naja atra, Trimeresurus stejnegeri, and Protobothrops mucrosquamatus—belong to the category 1, whereas the other two —Deinagkistrodon acutus and Daboia russelii siamensis—belong to the category 2 [7]. There are approximately 1,000 envenoming incidents in Taiwan each year, about 23.5–36% of which are N. atra envenoming [6, 8]
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