Important effects of Botulinum Neurotoxins on Central Nervous System

Important effects of Botulinum Neurotoxins on Central Nervous System
Bacterial toxins are often used as pharmaceuticals. Botulinum neurotoxins (BoNT) and tetanus neurotoxins (TeNT) are bacterial neurotoxins from the family of clostridial neurotoxins which are used for different human disease and disorders. Fascinating characteristics of these neurotoxins has made them attractive subjects for cellular physiology studies. Although exposure of toxins or poisonous substances to human’s body can cause suffering and death, these substances can also be used to cure human diseases . Understanding the cellular mechanism of action of toxins can uncover the capabilities of these substances to benefit human. Object of this paper is to discuss the cellular mechanism of action in neurons and also effects of BoNTs on the central nervous system.
Cellular mechanism of action in neurons--Afarvardin (talk) 05:08, 20 November 2012 (UTC)
TeNT and BoNTs are organized into heavy and light chains that are linked by disulphide bond and non-covalent interactions. Binding and interactions of neurotoxins to neurotransmitters is the main cause of disease. The absolute neurospecificity determines the level of their toxicity. We can divide mechanism of actions into 4 steps, 1) binding to the membrane 2) sorting to specific intracellular routes, 3) translocation process and 4) intracellular action. 1-Binding of TeNT receptors to neurons is mediated by lipid micro domains. In nerve cells, TeNT binds with polysialogangliosides and GPI-anchored proteins.
2-Binding is followed by sorting to specific intracellular routes when the toxic substances are targeted towards distinct regions of motor neurons, where they block the release of acetylcholine which is one of the neurotransmitters used in somatic nervous system. Fig1. Binding, internalization, translocation and intracellular action of tetanus neurotoxins on neuronal cell
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3- Translocation process of light chain (50 kDa) is associated with N-terminal of portion of heavy chain (HN ). Acidity of the N-terminal (lowering the PH) causes a conformational change in heavy chain which enables its insertion into the lipid bilayer.
4- Once the L-chain is in the cytoplasm, it can cleave the respective SNARE protein. For instance, BoNT -A and E cleave SNAP-25, BoNT cleaves Syntaxin 1and other BoNTs serotypes act on synaptobrevin.
Effects of BoNTs on the central nervous
Despite the long distances of neuromuscular junction to the central nervous system (CNS), high doses of BoNTs can affect the brain structure .Studies in alert behaving cats suggested that the injection of BoNT type A results in significant changes in discharge pattern of motor neurons . A research done on monkeys suggested that BoNT/A effects the cortical electrical activities. When all the vital signs were recorded spontaneously electrocardiogram (ECG), respiration, blood pressure and heart rate of animals did not change and only the electroencephalogram (EEG) showed abnormalities due to current changes within the neurons of brain . Even though many studies supports the effects of neurotoxins on central nervous system, cellular mechanisms of action of neurotoxins effect on central nervous system is has not yet been discovered.
Botulinum Neurotoxins received its first FDA approval as a pharmaceutical in 1989, about hundred and seventy years after Justinus Kermer proposed that sausage poisoning is caused by a biologic toxin . Research process in which a substance can be established as a pharmaceutical can be long and also very challenging. Understanding the mechanism of action is important not only to verify the capabilities of toxins to cure but also to avoid generation of disorders due to high level of neurospecificity. Today, Botulinum Neurotoxins are used to cure different disease and disorders such as dystonia, glabellar lines, hyperhidrosis and migraine headaches . Strong indication of recent studies on the effect of BoNT on brain cells caused many to expect the future use of neurotoxins to cure different brain diseases.
References:
Pellett, S. (2012). Learning from the past: historical aspects of bacterial toxins as pharmaceuticals. Current opinion in microbiology.
Lalli, G., Bohnert, S., Deinhardt, K., Verastegui, C., & Schiavo, G. (2003). The journey of tetanus and botulinum neurotoxins in neurons. TRENDS in Microbiology, 11(9), 431-437.
Caleo, M., & Schiavo, G. (2009). Central effects of tetanus and botulinum neurotoxins. Toxicon, 54(5), 593-599.
Moreno-Lopez, B., Pastor, A. M., De La Cruz, R. R., & Delgado-Garcia, J. M. (1997). Dose-dependent, central effects of botulinum neurotoxin type AA pilot study in the alert behaving cat. Neurology, 48(2), 456-464.
Polley, E. H., Vick, J. A., Ciuchta, H. P., Fischetti, D. A., Macchitelli, F. J., & Montanarelli, N. (1965). BOTULINUM TOXIN, TYPE A: EFFECTS ON CENTRAL NERVOUS SYSTEM. Science (New York, NY), 147(3661), 1036

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