Tetanus toxin activity

Burton, R. M., and Balfour, Y. M., 1962, Tetanus toxin activity and ganglioside content of rat brain, Biochem. Pharmacol. 11 974. 

Tetanus is a disease caused by the release of neurotoxins from the anaerobic, spore-forming rod Clostridium tetani. The clostridial protein, tetanus toxin, possesses a protease activity which selectively degrades the pre-synaptic vesicle protein synaptobrevin, resulting in a block of glycine and y-aminobutyric acid (GABA) release from presynaptic terminals. Consistent with the loss of neurogenic motor inhibition, symptoms of tetanus include muscular rigidity and hyperreflexia. The clinical course is characterized by increased muscle tone and spasms, which first affect the masseter muscle and the muscles of the throat, neck and shoulders. Death occurs by respiratory failure or heart failure. 

Altered release. Tetanus is an infectious disease caused by the bacterium Clostridium tetani. This bacterium produces a neurotoxin active on inhibitory synapses in the spinal cord. Motor neurons, which supply skeletal muscle and cause contraction, have cell bodies that lie in the spinal cord. Under normal circumstances, these motor neurons receive excitatory and inhibitory inputs from various sources. The balance of these inputs results in the appropriate degree of muscle tone or muscle contraction. Tetanus toxin prevents the release of gamma amino butyric acid (GABA), an important neurotransmitter active at these inhibitory synapses. Eliminating inhibitory inputs results in unchecked or unmodulated excitatory input to the motor neurons. The resulting uncontrolled muscle spasms initially occur in the muscles of the jaw, giving rise to the expression lockjaw. The muscle spasms eventually... 

Compared to people in a noncontaminated area, plasma IgG levels were also significantly decreased in proportion to increasing plasma levels of TCDD in a cohort exposed in an industrial accident in Seveso, Italy.118 There was no effect on IgM or IgA levels, or on complement levels IgE was not measured. In separate studies, in vitro exposure to TCDD enhanced the spontaneous production of IgE by B cells isolated from atopic but not non-atopic individuals, but did not affect the levels of other isotypes.119 Other recent studies have reported small changes in immune cells from individuals exposed occupationally to PHAH.120121 For example, compared to unexposed controls, a cohort of men exposed occupationally to TCDD had diminished IFNy production in a recall response to tetanus toxin, while IFNy production following polyclonal activation was unaffected.120 This observation is consistent with mouse studies, in which antigen-specific responses are highly suppressed by TCDD, but mitogen-driven T cell responses are less susceptible to impairment.83 88122123... 

Compared to polyclonal antibodies, mAbs display molecular homogeneity and significantly higher specificity leading to increased in-vivo activity. For example, 100-170 mg serum containing polyclonal antibodies against the tetanus toxin are necessary to achieve the same effect as 0.7 mg of a respective mAb. This section will provide an overview on therapeutic antibodies which have either been approved or are in clinical development, and will classify them according to different pharmacodynamically relevant properties. 

Induction of active immunity against diphtheria and tetanus toxins and pcitassis from age 6 weeks up to the seventh biithdav... 

Schiavo G, Poulain B, Rossetto O, Benfenati F, Tauc L, Montecucco C (1992 b) Tetanus toxin is a zinc protein and its inhibition of neurotrasmitter release and protease activity depend on zinc. In EMBOJ. 11 3577-83 Schiavo G, Rossetto O, Santucci A, DasGupta BR, Montecucco C (1992 c) Botulinum neurotoxins are zinc proteins. In J. Biol. Chem. 267 23479-83 Schiavo G, Rossetto O, Catsicas S, Polverino de Laureto P, DasGupta BR, Benfenati F, Montecucco C (1993 a) Identification of the nerve-terminal targets of botulinum neurotoxins serotypes A, D and E. In J. Biol. Chem. 268 23784-7 Schiavo G, Santucci A, DasGupta BR, Metha PP, Jontes J, Benfenati F, Wilson MC, Montecucco C (1993 b) Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. In FEBS Lett. 335 99-103 Schiavo G, Shone CC, Rossetto O, Alexandre FCG, Montecucco C (1993 c) Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synOp-tobrevin. In J. Biol. Chem. 268 11516-9... 

Certain other substances (tetanus toxin) reach nerve cells directly via distal axonal entry. Tetanus toxin is transported to the spinal anterior horn cell, subsequently translocates and binds to presynaptic inhibitory (glycinergic) nerve terminals impinging on the motor nerve cell, and thereby suppresses the inhibition of motor neuron activity leading to hyperexcitation. Violent and sustained muscle contraction (tetany) results in response to external stimulation. Another example of peripheral entry to the CNS is the transport and delivery of metals (manganese, aluminum) from the nose along olfactory neurons to the brain of laboratory animals. 

In Austria, the Serotherapeutical Institute was founded under the direction of R. Paltauf in 1894 to provide the necessary vaccines against diphtheria and tetanus. In their first research activities in this establishment, E. Loewenstein and M. Eisler von Terramare [27] discovered that the toxicity of tetanus toxin could be eliminated when treated with formaldehyde, thus enabling passive and active immunization. 

Finally, the enzymatic activity of botulinum toxin. A critical key to the identification of this enzymatic activity was provided by the cloning and sequencing of tetanus toxin and all seven serotypes... 

We later showed that C3 and neurotoxins are distinct entities. Purified botulinum neurotoxins and tetanus toxin have no ADP-ribosyltransferase activity. Furthermore, C3 and Cl are antigenically unrelated (1). It seems likely that the previously observed enzyme activity of the neurotoxins (2,3)... 

Finally, the naturalness of proteins does not necessarily make them safe some of the substances with the most powerful biological activity and potential toxicity are peptides and polypeptides (e.g., endorphins, tetanus toxin) and some proteins are known to cause allergic reaction after ingestion (e.g., milk casein, egg albumin, wheat gluten). 

Tea has been reported to have antiathero-sclerotic effects, vitamin P activities, and others. More recently reported effects include gastroprotective/antiulcer, estrogenic, immunomodulatory, antiallergic, and neuromuscular-protecting effect against botulinum and tetanus toxins. There also indications of possible benefits of tea in reducing the side effects of diabetes. ... 

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