Abstract
Snake venom proteins, which are responsible for deadly snakebite envenomation, induce severe injuries including neurotoxicity, myotoxicity, cardiotoxicity, hemorrhage, and the disruption of blood homeostasis. Yet, many snake-venom proteins have been developed as potential drugs for treating human diseases due to their pharmacological effects. In this study, we evaluated the use of, an L-amino acid oxidase isolated from Cerastes cerastes snake venom CC-LAAO, as a potential anti-glioblastoma drug, by investigating its in vivo and in vitro pharmacological effects. Our results showed that acute exposure to CC-LAAO at 1 and 2.5 µg/mL does not induce significant toxicity on vital organs, as indicated by the murine blood parameters including aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) activities, and creatinine levels. The histopathological examination demonstrated that only at high concentrations did CC-LAAO induce inflammation and necrosis in several organs of the test subjects. Interestingly, when tested on human glioblastoma U87 cells, CC-LAAO induced a dose-dependent apoptotic effect through the H2O2 generated during the enzymatic reaction. Taken altogether, our data indicated that low concentration of CC-LAAO may be safe and may have potential in the development of anti-glioblastoma agents.
Highlights
The World Health Organization (WHO) has included envenomation by snake bites in their list of neglected tropical diseases because it has been associated with significant morbidity and mortality, especially in tropical and subtropical areas [1]
To determine the safety concentration of CC-L-amino acid oxidases (LAAOs), which could eventually be used for therapeutic purposes, six male Swiss albino mice, per group, were injected by intraperitoneal route with different concentrations of CC-LAAO, and the physiological observations were reported to evaluate their general health status
As an initial step of general observation, we found that 500 μg/mL of CC-LAAO induced 100% mortality 2 h post-injection, whereas no signs of toxicity were recorded in the groups of mice injected with 1 μg/mL (M1); 2.5 μg/mL (M2); 10 μg/mL (M3); or 50 μg/mL (M4) after 24 h post-injection
Summary
The World Health Organization (WHO) has included envenomation by snake bites in their list of neglected tropical diseases because it has been associated with significant morbidity and mortality, especially in tropical and subtropical areas [1]. Snake venoms are mainly composed of enzymes such as phospholipases A2 (PLA2s), metalloproteases (SVMPs), serine-proteases (SVSPs), hyaluronidases, and L-amino acid oxidases (LAAOs). PLA2s have been shown to induce local myonecrosis and lymphatic vessel damage [5], and SVMPs are responsible for local hemorrhage, extracellular matrix degradation, blistering, and skin necrosis [6]. Costal-Oliveira et al demonstrated that LAAO from Bothrops atrox snake venom, triggers autophagy, apoptosis, and necrosis in normal human keratinocytes [10]. This finding contributes to a better understanding of LAAOs’ mechanisms of action and provides insights into its contribution to localized tissue necrosis during envenomation
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