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Toxins is defined as a poisonous substance that is produced by a living organism. Each toxin has the ability to bind specifically to a receptor and either blocks or opens the receptor. Medicine on the other hand serves to counteract the action of toxins and is commonly used in medical diagnosis, prevention and treatment of disease. One of the toxins is Î±-bungarotoxin (Î±-BGT). This toxin as described by Quik & Trifaro (1982) binds irreversibly with nicotinic acetylcholine receptor (nAchR) and trophic receptor. The Î±-BGT toxin usually affects the brain cells such as the chromaffin cells (Quik et. al, 1986). This poison can be countered by the effect of d-tubocurarine which is a nicotinic receptor blocker as it is a nicotinic receptor antagonist (Afar et. al, 1994). They will compete with the Î±-BGT for the binding site of the nicotinic receptor thus reducing the amount of Î±-BGT bound. An important point to here is the infectivity of nicotine despite it being a nicotinic agonist. The binding of Î±-BGT seems to be insurmountable despite high level of nicotine (Garza et. al, 1987). Another toxin considered as an antagonist is the cobratoxin (Î±-CTx) which binds antagonistically to the Î±7 nAchR. Zhang et. al (2012) and Konstantakaki et. al (2007) explains that this toxin when bounded to the receptors in the peripheral nervous system or the CNS has an analgesic effect as they have the ability to paralyze muscles to relieve pain, although the specific mechanism is not known. However, the antinociceptive action of Î±-CTx can be countered by atropine which is a non-selective muscarinic acetylcholine receptor (mAchR) (Zhang et. al, 2012). Atropine works by blocking the mAchR thus preventing the Î±-CTx from binding to the receptor. This can be proven by the study by Cheng et. al (2009) which showed that atropine administered after the toxin had no effect in inhibiting the effect of the toxin but pre-treatment by atropine blocked the action of Î±-CTx.
2.0 Toxins that function as sodium channel blockers
Another toxin being used as an analgesic is the tetrodotoxin (TTX) particularly in cancer treatment. TTX functions as a sodium channel blocker which is found on most nociceptive pain fibres and therefore is thought to be related to its analgesic effect (Hagen et. al, 2008). Stummann et .al (2005) states that there are two types of voltage-gated Na+ currents, the tetrodoxin-sensitive and the tetrodotoxin-resistant, both of which are commonly expressed in the dorsal root ganglion neurons. However, the tetrodotoxin binds to the tetrodotoxin-sensitive Na+ channels with much higher affinity than the latter. These receptors can also be found in myocytes and if bound to the TTX will prevent the contraction of the muscles. Anti-cholinesterase is often used to treat TTX as they prevent the breakdown of acetylcholine and this increases the action of neurotransmitter acetylcholine (Anon., 1997). Another medication that can be used is muscarine, which mimics the action of acetylcholine by binding onto muscarinic acetylcholine receptor. Muscarine has the ability to depolarize neurons resulting in a higher action potential and reverse the effect caused by tetrodotoxin which actually prevents the depolarization of neurons (Nowak & McDonald, 1983). Cardiac glycosides can also be used to treat TTX as they function to increases heart contractility which is the opposite of the effect of TTX (more information on cardiac glycoside can be found in 2.1)
2.1 Cardiac glycosides that has the ability to reverse the effect of toxins (therapeutic actions)
Cardiac glycoside also represents another type of medication commonly used to treat congestive heart failure and cardiac arrhythmia. Ouabain and digoxin are both cardiac glycoside and therefore only affects heart muscles, myocytes. Both these medication functions is the same way as they both inhibit the Na+/K+ ATPase pump (Kohls et. al, 2012). The inhibition of the pump causes an increase in the concentration of Na+ in the myocytes. Calcium on the other hand is left in the myocytes and unable to leave as they are dependant on the flow of Na+ into the myocytes which is usually facilitated by the Na+/Ca2+ pump. The increase concentration of Ca2+ in the myocytes increases the heart contractility and force of contraction.
3.0 Toxins that function as potassium channel blockers
Other neurotoxins such as the mast cell degranulating peptide (MCDP) has a anti-inflammatory activity. This toxin binds to the mast cells causing it to degranulate and release histamine at low MCDP concentration while a high concentration it has anti-inflammatory properties closely related to a type 1 hypersensitivity reaction (Buku, 1999). Other than that, MCDP is also able to inhibit voltage-dependant K+ channel (KV channel) in brain membranes (Kondo et. al, 1992). A study by Horiuchi et. al (2012), showed that inhibition of the KV channel significantly reduced diameter of a rat basilar and cerebral arteries. This shows that the KV channel pays a significant role in the regulation of brain arteriolar tone. Bidard et. al (1989) states that MCDP is not the only neurotoxin to bind to the KV channel, they showed that dendrotoxin (DTX) also binds to the same type of receptor in motor neurons. Hence, both these neurotoxins affects the nervous system in a similar fashion, by inducing epileptiform activity and paroxystic seizures (Bidard et. al, 1989). In other words, both these neurotoxins have the ability to increase the concentration of acetylcholine release at neuromuscular joints which will prolong action potentials thus resulting in hyperexcitability of muscles. Charybdtoxin (CTX) is another neurotoxin that has the ability to block the potassium channels but unlike MCDP and DTX, it blocks the calcium-activated potassium channels (KCa channel) (Visan et. al, 2004). They bind to the extracellular site of the channel and occlude the channel pores by binding to one of the four independent sites (Visan et. al, 2004). The binding of CTX causes a contraction that is concentration dependant of the arteries in the brain similar to MCDP (Asano et .al, 1994). The binding of CTX to the KCa channel causes the channel to be unable to be activated by Ca2+ and prevents the depolarization of the membrane (Horiuchi et. al, 2012). All three of this neurotoxin causes hyperexcitability in neurones as well as muscles due to the oversecretion of acetylcholine. Therefore, atropine which is an anti-cholinergic drug can be used to counteract the action of these neurotoxins. They inhibit parasympathetic nerve impulses by blocking the binding of neurotransmitter acetylcholine as they are competitive antagonist of acetylcholine thus preventing hyperexcitability of the neurons or muscle.
4.0 Toxins that function as G-coupled protein inhibitors
The next group of neurotoxins are toxins that originate from bacteria, more specifically toxins of type AB5-type exotoxin. The first toxin is the cholera toxin isolated from Vibrio cholerae and the other toxin is pertussis toxin (PT) from Bordetella pertussis. Both these toxins A and B domain with the A domain has enzymatic activity and is transferred to the host cell while the B domain is responsible for binding to the receptor of the host cell (Miller, 1994). The infection process begins with the binding of the toxin to specific GM1 gangliosides on the mucosal cells in the intestine. This in turn stimulates the production of intestinal adenyl cyclase activity, catalysed by the ADP-ribosylation of the GÎ±s subunit resulting in a net production of electrolytes and water from the body leading to severe diarrhea and water loss (Barua & Greenough, 1992). The cholera toxin can be inhibited by a polypeptide consisting of multiple oligo-GM1 and poly-L-lysine, they do this by preventing the cholera toxin from adhereing to the GM1 receptors (Thompson & Schengrund, 1998). PT enters a cell by binding to the cell surface receptor and entering via endocytosis. The difference between PT and cholera toxin is that PT catalyzes the ADP-ribosylation of the GÎ±i subunit leading to an increase in cAMP formation (Fowler et. al, 2003). The biological effects relating to PT in vivo is histamine sensitization, increase in vascular permeability and islet activation (Aktories, 2008). Formaldehyde is one of the treatment for PT, in the presence of lysine it causes a covalent modification to the S1 subunit of PT thus causing detoxification (Fowler et. al, 2003).
5.0 Toxins that functions as protein phosphatase inhibitors
Okadaic acid (OA) is another type of toxin that causes shellfish poisoning. OA works by inhibiting protein phosphatase 1 and 2A in cells by its trans-C8-diol ester side group (Wera et. al, 1993 & Miles et. al, 2006). Phosphatase are enzyme which help remove a phosphate group from its substrate by enzymatic action. Phosphatase plays an important role in signal transduction pathway as they are actively regulating protein that they control. Therefore, the inhibition of phosphatase can deactivate a crucial enzyme and therefore upset the signal transduction pathway. OA can be treated using a channel antagonist nimodipine, they work by binding to specific L-type voltage gated calcium channels (Ekinci et. al, 2003). This reverses the action of OA and prevents the inhibiton of protein phosphatase.