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Neuroinfectious Diseases
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Jeremy D. Young, Jesica A. Herrick, Scott Borgetti
Tetanospasmin (tetanus toxin) binds at the presynaptic terminals of lower motor neurons, causing peripheral neuromuscular failure (localized tetanus). The toxin is then carried by retrograde axonal transport to neurons in the spinal cord and brainstem, where toxin binds irreversibly. In the CNS, tetanus toxin enters the terminals of inhibitory (e.g. GABAergic) neurons. Synaptobrevin is degraded by the toxin, inhibiting the docking of vesicles containing neurotransmitters with the synaptic membrane, preventing neurotransmitter release. Tetanospasmin produces muscular rigidity by raising the resting firing rate of motor neurons via loss of inhibition, and generates spasms by failing to limit reflex responses to afferent stimuli. In the autonomic nervous system, a hypersympathetic state predominates, with a failure to inhibit the adrenal release of catecholamines. Toxin binding is a terminal and irreversible event. Recovery from tetanus appears to depend on the sprouting of a new axon terminal, which takes months.
Medical Countermeasures for Intoxication by Botulinum Neurotoxin
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Michael Adler, Ajay K. Singh, Nizamettin Gul, Frank J. Lebeda
The underlying mechanisms that generate synchronous release at neuromuscular synapses are complex (Atlas, 2013; Nishiki and Augustine, 2004), and the respective roles of the BoNT substrates SNAP-25 and synaptobrevin in regulating the transition between asynchronous and synchronous release are not well understood. From observations that transmitter release in BoNT/A-intoxicated muscles can be rescued by procedures that elevate intracellular Ca2+ (Cull-Candy et al., 1976; Lundh et al., 1977; Molgó et al., 1980), it has been suggested that the BoNT/A-truncated SNAP-25, having only a nine–amino acid C-terminal deletion, has the potential for promoting transmitter release if Ca2+ concentrations are sufficiently elevated at transmitter release sites (Adler et al., 1995; Bradford et al., 2018). Thus, enhanced Ca2+ entry may be an important factor in a transition between asynchronous and synchronous release mechanisms.
SBA Answers and Explanations
Published in Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury, SBAs for the MRCS Part A, 2018
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury
Tetanus is typically a disease of soldiers, farmers, or gardeners. It is caused by deep penetrating wounds caused by objects contaminated with soil, which introduces spores into the tissue. As soon as the wound becomes anaerobic, the tetanus spores germinate to produce vegetative cells, which then multiply and release a potent neurotoxin called tetanospasmin. Only the tiniest quantities of exotoxin are required for the disease to develop. The bacteria producing the exotoxin are entirely non-invasive and lack all other virulence factors apart from the capacity to produce toxin. The exotoxin binds to local nerve endings, travels up the axon to the spinal cord, traverses a synaptic junction, and finally gains entry to the cytoplasm of inhibitory neurones. Within these cells the toxin exerts a highly specific proteolytic activity on one of the proteins (synaptobrevin) present in the vesicles that is responsible for the normal trafficking of inhibitory neurotransmitter to the synaptic junction. As a result, the inhibitory neurone cannot transmit its impulse and there is unopposed stimulation of skeletal muscles by motor neurones. Death is normally due to muscular spasm (spastic paralysis) extending to involve the muscles of the chest so that the patient is unable to breathe.
The neurosciences at the Max Planck Institute for Biophysical Chemistry in Göttingen
Published in Journal of the History of the Neurosciences, 2023
The Max Planck Society, unfortunately, could not offer Jahn an adequate position after his post as head of the Junior Investigators Group in Munich expired, and he returned to the United States. There, he was at the Yale University School of Medicine from 1991 to 1997, his last position being professor of pharmacology and cell biology. During this time, he made important contributions toward identifying synaptotagmin (previously P65) as a Ca2+ sensor in the release of neurotransmitters (Brose et al. 1992). He was also able to demonstrate how neurotoxins like tetanus toxin or botulinum toxin inhibit the release of neurotransmitters by interacting with synaptobrevin, syntaxin, or SNAP 25 (Blasi et al. 1993). In 1995, Jahn was appointed a scientific member and director of the Department for Neurobiology at the MPI for Biophysical Chemistry, taking up his work in Göttingen in 1997.25Reinhard Jahn was appointed to the MPI for Biophysical Chemistry as a scientific member and director on March 24, 1995, in the first round and on June 22, 1995, in the second round by the Senate of the Max Planck Society. See the minutes of the 139th session of the Senate from March 24, 1995, in Berlin, AMPG, II. Abt., Rep. 60, Nr. 139, as well as the minutes of the 140th session of the Senate from June 22, 1995, in Potsdam, AMPG, II. Abt., Rep. 60, Nr. 140.
Pain in cervical dystonia: mechanisms, assessment and treatment
Published in Expert Review of Neurotherapeutics, 2021
Raymond L. Rosales, Lorraine Cuffe, Benjamin Regnault, Richard M. Trosch
In the medium term, new treatments that take advantage of the diverse BoNT family of proteins are under development [118,119]. SNARE proteins are a family of proteins involved in regulating exocytosis, which in neurons mediate neurotransmitter release. Each BoNT serotype (types A-G) specifically cleaves one SNARE protein (SNAP25 and synaptobrevin, except for BoNT-C which can cleave both), thus inhibiting synaptic vesicle exocytosis and neurotransmission at the neuromuscular junction in different ways [118,120]. This natural diversity offers the potential to modify clinical properties of BoNT proteins to meet the needs of patients living with a variety of movement disorders, including CD, and it is conceivable that some products will have greater (or lesser) effects on pain mechanisms than others [120]. Moreover, protein engineering offers a huge potential for new BoNTs with enhanced clinical properties. For example, it appears possible to improve the neuronal binding of Type A [121,122], enhance the catalytic activity of Type B [123] and enhance the syntaxin-specific catalytic activity of Type C [124]. Looking even further forward, with BoNTs as their scaffold, targeted secretion inhibitors are a new class of biopharmaceuticals that can inhibit cellular secretion for very prolonged periods of time [125,126] and therefore may also offer new potential for patients living with painful chronic conditions.
Exploring the role of botulinum toxin in critical care
Published in Expert Review of Neurotherapeutics, 2021
Muhammad Ubaid Hafeez, Michael Moore, Komal Hafeez, Joseph Jankovic
There are eight BoNT serotypes termed A to H, out of which BoNT-A has been most frequently used, followed by BoNT-B [1,2,5]. All serotypes act by cleaving neuronal vesicle-associated proteins, called SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Serotypes A, C, and E cleave SNAP-25 (synaptosome-associated protein of 25kd) while type B, G, D, E, and H cleave synaptobrevin. Type C also cleaves syntaxin [5]. The cleavage prevents acetylcholine vesicle fusion with presynaptic membrane, thus preventing its exocytosis, resulting in focal neuromuscular blockade [1]. The onset of action is variable for different clinical indications ranging from 1 to 2 days for strabismus to up to two weeks for cervical dystonia [1]. The effect typically lasts only 3 to 4 months due to sprouting of new axonal terminals and loss of effect on old terminals [1]. Immunoresistance due to development of blocking antibodies can be a rare cause of secondary unresponsiveness in patients who previously benefited from BoNT [6].