Abstract
Snakebite envenoming is an important public health problem in many tropical and subtropical countries, and is considered a neglected tropical disease by the World Health Organization. Most severe cases are inflicted by species of the families Elapidae and Viperidae, and lead to a number of systemic and local effects in the victim. One of the main problems regarding viperidic accidents is prominent local tissue damage whose pathogenesis is complex and involves the combined actions of a variety of venom components. Phospholipases A2 (PLA2s) are the most abundant muscle-damaging components of these venoms. Herein, we report functional and structural studies of PrTX-I, a Lys49-PLA2 from Bothops pirajai snake venom, and the influence of rosmarinic acid (RA) upon this toxin's activities. RA is a known active component of some plant extracts and has been reported as presenting anti-myotoxic properties related to bothopic envenomation. The myotoxic activity of Lys49-PLA2s is well established in the literature and although no in vivo neurotoxicity has been observed among these toxins, in vitro neuromuscular blockade has been reported for some of these proteins. Our in vitro studies show that RA drastically reduces both the muscle damage and the neuromuscular blockade exerted by PrTX-I on mice neuromuscular preparations (by ∼80% and ∼90%, respectively). These results support the hypothesis that the two effects are closely related and lead us to suggest that they are consequences of the muscle membrane-destabilizing activity of the Lys49-PLA2. Although the C-terminal region of these proteins has been reported to comprise the myotoxic site, we demonstrate by X-ray crystallographic studies that RA interacts with PrTX-I in a different region. Consequently, a new mode of Lys49-PLA2 inhibition is proposed. Comparison of our results with others in the literature suggests possible new ways to inhibit bothropic snake venom myotoxins and improve serum therapy.
Highlights
Envenoming resulting from snakebites is an important public health problem in many tropical and subtropical countries [1,2]
The neuromuscular blockade induced by PrTX-I was not reversed when preparations were washed for 30 minutes with toxin-free physiological solution
Preparations exposed to PrTX-I that had been pre-incubated with rosmarinic acid (RA) showed most fibers with normal aspects (Figures 2d, 4e and 4f); the muscle damage index was 7.960.9% (Figure 3)
Summary
Envenoming resulting from snakebites is an important public health problem in many tropical and subtropical countries [1,2]. Data on this topic are scarce, a recent study estimates that at least 421,000 envenomations and 20,000 deaths due to snakebites occur each year [2]. This problem is important in the rural tropics because the populations of these areas usually have poor access to health systems and, in some cases, antivenom is scarce [1,3]. Even though the majority of deaths due to snakebite envenoming occur in south and south-east
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