Oluwafemi Shittu Bakare* and Idowu Taye Lydia
Department of Biochemistry, Faculty of Science, Adekunle Ajasin University, Akungba Akoko, Ondo State, Nigeria
Received: 04 April 2024; Accepted: 21 April 2024; Published: 26 April 2024
Citation: Bakare, OS and Idowu Taye Lydia. “Molecular Mechanisms of Paralysis in Snakebite Envenomation: A Multifaceted Landscape.” J Healthc Adv Nurs (2024): 111. DOI: 10.59462/3068-1758.2.2.111
Copyright: © 2024 Bakare OS. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Snakebite envenomation poses a persistent global health threat, necessitating a comprehensive understanding of venom components, biochemical pathways leading to paralysis, distribution factors, diversity, and therapeutic interventions. This review integrates historical perspectives with contemporary insights to elucidate the multifaceted landscape of snakebite management. The investigation starts with a study of snake venom and all of its components, highlighting the complex biochemistry that gives them their power. The biochemical cascades that result in paralysis, namely those mediated by Three-Finger Toxins (3FTx) and Phospholipase A2s (PLA2s), are analyzed to elucidate the molecular mechanisms underlying rapid neuromuscular impairment. Variations in species and environmental variables that impact venom dispersal are examined in order to understand the intricacies of envenomation. The review traverses the wide range of snake venoms, acknowledging the influence of geographical variances on venom toxicity and composition. The main focus is on therapeutic techniques, with antivenom therapy being the most important one for more than a century. The mechanisms of action are examined, including possible limits and the creation of venom-antivenom complexes. Beyond antivenom, novel molecular interventions are discussed along with their potential to address the problems with treating snakebite.
Snakes, with their ancient evolutionary lineage and unparalleled adaptability, have coexisted with humans throughout history. While many species play vital roles in ecosystems, some pose a threat due to their venomous nature [1]. Snakebites, resulting from encounters with venomous snakes, represent a significant global health challenge. The World Health Organization (WHO, 2023) estimates that 4.5–5.4 million people get bitten by snakes annually. Of this, 1.8–2.7 million develop clinical illness and 81,000 to 138,000 die from complications. Many of these incidents occur in impoverished rural regions, emphasizing the critical need for research and interventions to mitigate the impact of snakebite envenomation.
Paralysis, a debilitating consequence of certain snakebites, compounds the severity of envenomation [2]. Snakes employ a diverse array of bioactive molecules within their venom, each designed to target specific physiological systems. Paralysis, as a clinical manifestation, underscores the urgency of understanding the intricate biochemistry of snake venom. It manifests as a disruption in the normal functioning of the nervous and muscular systems, leading to loss of motor control and, in severe cases, respiratory failure.
Snakebite envenomation, often neglected in discussions on global health, exacts a heavy toll on communities where venomous snakes are prevalent. Beyond the immediate physical impact, the socio-economic burden is substantial, with long-term consequences for affected individuals and their communities. The prevalence of snakebites is intricately linked to the geographic distribution of venomous snake species, with higher incidence rates reported in tropical and subtropical regions [3]. Understanding the biochemical basis of snake venom and its role in paralysis is pivotal for developing effective prevention and treatment strategies. The biochemistry of snake venom encompasses an intricate interplay of proteins, enzymes, peptides, and other bioactive molecules [4].
Objectives
This review aims to address the following objectives:
1. Understanding the composition of snake venom: By providing a comprehensive overview of the components of snake venom, including proteins, enzymes, peptides, and other bioactive molecules, we aim to establish a foundation for understanding the biochemical basis of paralysis.
2. Examine the mechanisms of venom action: Indepth exploration of how snake venom components interact with the human body will uncover the biochemical processes that lead to paralysis. This includes a detailed discussion of neurotoxic and myotoxic components.
3. Investigate enzymatic activity: Detailing the enzymatic activities present in snake venom and highlighting specific enzymes will provide insights into their effects on physiological processes and their role in paralysis.
This comprehensive exploration aims to contribute to the growing body of knowledge surrounding the biochemistry of snake venom and its implications for paralysis, ultimately informing strategies for snakebite prevention and treatment.
Composition and diversity of snake venom
Overview of Venom Components: Snake venom is a sophisticated mixture of hundreds of different pharmacologically active molecules, including lowmolecular- mass compounds (e.g., histamine and alkaloids), small peptides, and proteins, each with a distinct role in envenomation [5]. This section provides an in-depth examination of the major components found in snake venom, emphasizing the diversity and complexity of these substances.
Phospholipase A2s (PLA2s): Phospholipases are a group of enzymes found in snake venom that play a crucial role in disrupting cell membranes. Specifically, phospholipase A2s (PLA2s) are a prominent component of snake venom. These enzymes are known for their ability to hydrolyze the sn-2 ester bond of glycerophospholipids, leading to the release of fatty acids and lysophospholipids. This activity can disrupt cell membranes, leading to a range of physiological effects including tissue damage, inflammation, and neurotoxicity [6]. Some PLA2s specifically target neuronal cells. By disrupting the integrity of neuronal membranes, these enzymes interfere with nerve signal transmission, leading to the impairment of neural communication. This disruption contributes to the rapid onset of paralysis observed in snakebite victims.
Furthermore, PLA2s have been found to exhibit multiple pharmacological functions, and their structural studies have contributed to our understanding of their catalytic mechanisms and inhibition. The acidic and basic subunits of viperotoxin F and vipoxin, for example, have been shown to play multifunctional roles, affecting the neurotoxicity and enzymatic activity of the PLA2 [7].
Serine proteinases: Serine proteinases are another group of enzymes found in snake venom that play a crucial role in various physiological reactions. These enzymes are composed of approximately 245 amino acid residues and contain two-six-stranded b-barrels that have evolved by gene duplication. Similar to chymotrypsin-like serine proteinases, the structures of snake venom serine proteinases (SVSPs) consist of an N-terminal subdomain composed of six b-strands, as well as a short a-helix positioned between strands 3 and 4 on which the catalytic residue His57 is located.
SVSPs have been found to participate in various physiological reactions, including blood coagulation, digestion, and the immune response. They have also been used as important tools in the study of haemostasis and are clinically used for clotting assays, diagnosis, determination of protein C, protein S, plasma fibrinogen, study of platelet function, as defibrinogenating agents, to investigate dysfibrinogenemia, test the contractile system of platelets, and for defibrinogenation of plasma These enzymes are involved in various physiological reactions and can contribute to the immobilization of prey [8].
Acetylcholinesterase (AChEs): Acetylcholinesterase found in snake venom play a significant role in the paralysis and immobilization of prey. AChE is a member of the cholinesterase family and is vital in terminating the chemical impulse of acetylcholine (ACh) transmission in the nervous system by hydrolyzing ACh to choline and an acetate group, thereby terminating the chemical impulse [9]. The rapid hydrolysis of ACh forms the basis of rapid, repetitive responses at the synapse, and AChE may also be one of the fastest enzymes known, hydrolyzing ACh at a rate close to the diffusion-controlled rate [9].
In the context of snake venom, the presence of AChE contributes to the venom’s ability to disrupt neuromuscular transmission, leading to paralysis and immobilization of the prey. This effect is achieved by interfering with the normal function of ACh in propagating an electrical stimulus across the synaptic junction, ultimately leading to paralysis and incapacitation of the prey [10].
L-amino acid oxidases (LAAOs): These are enzymes found in snake venom that are involved in the oxidative deamination of L-amino acids. These enzymes can induce apoptosis in certain cells and have been found to exhibit a range of pharmacological effects [11]. LAAOs are also known for their ability to generate hydrogen peroxide, which can contribute to the cytotoxic effects of the venom [11]. The study of LAAOs in snake venom is of great interest to researchers due to their potential medical applications. For example, LAAOs have been found to exhibit anti-tumor activity and have been investigated as potential therapeutic agents for cancer treatment [11]. Additionally, the structural studies of LAAOs have contributed to our understanding of their catalytic mechanisms and inhibition, which has implications for the development of potential inhibitors and lead compounds with therapeutic applications [11].
Snake venom metalloproteinases (SVMPs): They are a group of enzymes found in snake venom that play a crucial role in various physiological effects, including tissue damage, inflammation, and disruption of the extracellular matrix. These enzymes are known for their ability to degrade components of the extracellular matrix, such as collagen, and are implicated in the pathogenesis of snake envenomation [12]. Metalloproteinases contribute to the toxicity of the venom by disrupting the integrity of tissues and blood vessels, leading to hemorrhage and tissue damage [12]. Additionally, metalloproteinases have been found to play a role in coagulopathy and hemostatic disturbances associated with snake envenomation [13].
Three-Finger Toxins (3FTx): Three-Finger Toxins are a diverse family of snake venom proteins known for their distinctive structural motif resembling three extended fingers. These toxins exert a wide range of effects, including neurotoxicity, and are implicated in the rapid paralysis observed in snakebite victims. 3FTx primarily target the nervous system, interfering with synaptic transmission. By binding to and modulating receptors on nerve cells, these toxins disrupt normal neural signalling. The result is a cascade of events leading to the rapid onset of paralysis. Beyond their neurotoxic effects, 3FTx can exhibit a variety of functional roles, such as blocking ion channels, affecting blood clotting, or even exerting cardiotoxic effects. The diversity in their actions underscores the complexity of snake venom biochemistry [14].
Diversity across snake species: Snake venom composition exhibits a remarkable diversity that is intricately linked to the unique ecological niches and evolutionary adaptations of different snake species [15]. Understanding this diversity provides crucial insights into the intricate interplay between venom biochemistry and the ecological roles of snakes.
Geographic distribution: The geographic range of a snake species significantly influences venom composition. Snakes inhabiting distinct regions may face different ecological challenges, leading to the evolution of venom with specific characteristics tailored to local prey and environmental conditions [16].
• Dietary habits and prey specialization: Venom is an adaptive trait shaped by a snake’s dietary preferences. Snakes that primarily prey on mammals may develop venoms rich in neurotoxic components, enabling rapid immobilization of warm-blooded prey. In contrast, those targeting amphibians or other reptiles may exhibit different venom profiles to suit their specific dietary requirements [15].
• Intraspecific variation and individual factors: Even within a single species, there exists notable intraspecific variation in venom composition. Factors such as age, sex, and individual variability contribute to this diversity, highlighting the complexity of the interplay between genetic factors and environmental influences.
Snake venom components causing paralysis
Snake venom, with its intricate blend of bioactive components, stands as a potent force capable of inducing paralysis in envenomed individuals. According to Bickler [14], Phospholipase A2s (PLA2s) and Three-Finger Toxins (3FTx) are responsible for paralysis during envenomation. In this chapter, we embark on an exploration of the biochemical pathways orchestrated by specific venom components, focusing on Phospholipase A2s (PLA2s) and Three-Finger Toxins (3FTx). This journey delves into the molecular intricacies that underlie the rapid onset of paralysis, shedding light on the interconnected pathways and their profound impact on the human body.
Biochemical pathway of pla2s causing paralysis: Phospholipase A2s (PLA2s), formidable enzymatic architects residing within snake venom, orchestrate a complex symphony of molecular events, ultimately culminating in the paralysis observed in snakebite victims [17] This intricate biochemical pathway unfolds with precision, influencing the delicate balance of cellular processes and prompting a cascade of physiological responses.
Initiation and targeting of cellular membranes
The journey begins with the initiation phase, where PLA2s, poised within the venom, strategically target cellular membranes. These enzymes exhibit a particular affinity for phospholipids, the building blocks of membranes. Through a process of hydrolysis, PLA2s cleave phospholipids at the sn-2 position, liberating fatty acids and lysophospholipids [17].
Neurotoxic effects: disruption of neural signalling
This liberation sets the stage for neurotoxic effects as the altered membrane integrity disrupts the normal functioning of nerve cells. PLA2s, acting as insidious infiltrators, interfere with the intricate dance of signals between neurons, initiating a rapid breakdown in neural communication. The consequences are profound, with manifestations ranging from numbness and tingling to the ultimate manifestation—paralysis [18] (Figure 1).
Figure 1. ECG
Biochemical pathway of three-finger toxins (3ftx) causing paralysis
Three-Finger Toxins (3FTx): Three-Finger Toxins (3FTx), a versatile family of venom proteins, intricately weave a biochemical tapestry that leads to the rapid onset of paralysis in snakebite victims. This pathway, laden with diversity and functional intricacies, unfolds as a dynamic interplay of molecular events, offering profound insights into the complex landscape of venom biochemistry [19]. In the scope of 3FTx, α-Neurotoxin found in the venom of the Black Mamba (Dendroaspis polylepis) demonstrates a remarkable ability to block ion channels [20]. This function influences the intricate balance of cellular homeostasis, showcasing the versatility embedded within the venomous arsenal. In another example, β-Neurotoxins, exemplified by Cobrotoxin from the Naja genus, influence the neuromuscular junction, contributing to the overall neurotoxic effects leading to paralysis [21].
Initiation and neurotoxic effects: The journey commences with 3FTx initiating their assault on the nervous system. An exemplary member of this family, α-Bungarotoxin from the Many-Banded Krait (Bungarus multicinctus), showcases this neurotoxic effect. By binding to and modulating nicotinic acetylcholine receptors on nerve cells, α-Bungarotoxin disrupts the delicate dance of neural signals, setting the stage for the swift onset of paralysis observed in snakebite envenomation [22].
Therapeutic approaches and future directions in snake venom-induced paralysis: For more than a century, antivenoms have been a cornerstone in the treatment of snakebite [12]. Antivenoms are immunoglobulin fractions (Fab or F(ab’)2) or polyclonal immunoglobulins (IgG) that are produced by immunizing animals, usually horses, with venom. Whole IgG antivenom is produced by regularly harvesting the resultant antibodies and separating the immunoglobulins from the blood. Using papain or pepsin digestion, commercial antivenoms can be further fractionated into Fab or F(ab’)2 [12]. Further purification procedures, such as chromatography and pasteurization, may come next, depending on the production process [23]. Antivenoms are usually injected intravenously and are available as liquid or freeze-dried powder. But the therapy is not without difficulties because some antivenoms are associated with severe responses, including potentially fatal ones.
Mechanisms of antivenom action: Antivenom molecules, mainly polyclonal antibodies, are anticipated to surpass venom molecules in the bloodstream at clinical dosages [24]. Antivenoms are polyclonal, which means they cover a variety of antibodies or antibody fractions against both neurotoxins and non-neurotoxic toxins. Antivenom molecules are administered, and upon binding with circulating toxins, venom-antivenom complexes are formed, which trap venom molecules within the circulation [25]. Antibodies in antivenom may function by inhibiting neurotoxins’ active sites, preventing their interaction with target sites (neuromuscular junction) by limiting their travel to extravascular target sites, and improving the removal of toxins from the body [26,27]. Furthermore, antivenom molecules may be able to go from the circulation to neuromuscular junctions, where they could neutralize neurotoxins at their specific locations. It is still unknown, though, how well Fab, F(ab’)2, or entire IgG distribute.
Challenges and limitations of antivenom therapy: While antivenom therapy holds promise, it faces challenges. Presynaptic neurotoxins cause irreversible structural damage to motor nerve terminals in the short term, making it unlikely for antivenom to reverse established presynaptic neurotoxic injury [19]. In contrast, postsynaptic neurotoxins, acting like reversible neuromuscular blockers, vary in the reversibility of binding to nicotinic acetylcholine receptors. Specific immunoglobulins in antivenom may enhance recovery of neuromuscular junctions from postsynaptic toxin-mediated neuromuscular block.
Antivenom therapy, while an essential component in snakebite treatment, continues to face challenges related to adverse reactions and limitations in reversing established neurotoxic injuries. Future research should focus on refining antivenom formulations, improving distribution to target sites, and exploring innovative interventions to enhance the overall efficacy and safety of snakebite treatments. Balancing these efforts can contribute to more effective management and prevention of snakebite envenomation.