Abstract
Neuro- and myotoxicological signs and symptoms are significant clinical features of envenoming snakebites in many parts of the world. The toxins primarily responsible for the neuro and myotoxicity fall into one of two categories—those that bind to and block the post-synaptic acetylcholine receptors (AChR) at the neuromuscular junction and neurotoxic phospholipases A2 (PLAs) that bind to and hydrolyse membrane phospholipids of the motor nerve terminal (and, in most cases, the plasma membrane of skeletal muscle) to cause degeneration of the nerve terminal and skeletal muscle. This review provides an introduction to the biochemical properties of secreted sPLA2s in the venoms of many dangerous snakes and a detailed discussion of their role in the initiation of the neurologically important consequences of snakebite. The rationale behind the experimental studies on the pharmacology and toxicology of the venoms and isolated PLAs in the venoms is discussed, with particular reference to the way these studies allow one to understand the biological basis of the clinical syndrome. The review also introduces the involvement of PLAs in inflammatory and degenerative disorders of the central nervous system (CNS) and their commercial use in the food industry. It concludes with an introduction to the problems associated with the use of antivenoms in the treatment of neuro-myotoxic snakebite and the search for alternative treatments.
Highlights
They are of particular interest to the neurologist and neurotoxicologist because secreted PLA2s (sPLA2) are intimately involved in the peripheral neuro-myotoxicity caused by envenoming bites by many dangerous snakes and because both s- and cytosolic PLA2s (cPLA2) are implicated in inflammatory and degenerative disease of the central nervous system (CNS) [3,4,5,6] Phospholipases A2 (PLA2) are widely used in the food processing industry for the refinement of oils and the processing of eggs, cereals and dairy produce and there is great interest in their possible use for the remediation of oil-contaminated land [7,8,9]
Like sPLA2s, the cPLA2s are Ca2+-activated but, unlike the sPLA2s, calcium is not required for catalytic activation but acts via an N-terminal domain involving Asp-37, Asp-43, Asp-93 and Glu-100 to promote the binding of the enzyme to lipid membranes
Prasarnpun et al 2004 have shown that depletion of the synaptic vesicles can be largely prevented by exposure to conotoxin ω-MVIIC, which selectively blocks the opening of P/Q type voltage-gated Ca2+ channels that populate the mammalian motor nerve terminals, and botulinum toxin C which hydrolyses syntaxin and SNAP-25, preventing the formation of SNARE complexes that underpin exocytosis [76] (Figure 15)
Summary
Phospholipases C cleave the glycerophosphate bond and phospholipases D remove the polar head group. PLA2s comprise a very large superfamily of enzymes composed of 16 recognised groups within six major types [1,2]. The enzymes are found in virtually all forms of life from bacteria to invertebrates, vertebrates and plants They play a major role in the regulation of phospholipid turnover, membrane fluidity and trafficking, cell maturation and maintenance, apoptosis, and the production of the eicosanoids, leukotrienes and prostaglandins. To the neurologist and neurotoxicologist because sPLA2s are intimately involved in the peripheral neuro-myotoxicity caused by envenoming bites by many dangerous snakes and because both s- and cPLA2s are implicated in inflammatory and degenerative disease of the CNS [3,4,5,6] PLA2s are widely used in the food processing industry for the refinement of oils and the processing of eggs, cereals and dairy produce (in which role they are not considered to pose any form of health risk) and there is great interest in their possible use for the remediation of oil-contaminated land [7,8,9]
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