Neurotoxin Inhibitor

Tetanus and tetanus neurotoxin: From peripheral uptake to central nervous tissue targets

Tetanus is a deadly but preventable disease caused by a protein neurotoxin produced by Clostridium tetani. Spores of C. tetani may contaminate a necrotic wound and germinate into a vegetative bacterium that releases a toxin, termed tetanus neurotoxin (TeNT). TeNT enters the general circulation, binds to peripheral motor neurons and sensory neurons, and is transported retroaxonally to the spinal cord. It then enters inhibitory interneurons and blocks the release of glycine or GABA causing a spastic paralysis. This review attempts to correlate the metalloprotease activity of TeNT and its trafficking and localization into the vertebrate body to the nature and sequence of appearance of the symptoms of tetanus.

Conversion Ratio between Botox?, Dysport?, and Xeomin? in Clinical Practice

Botulinum neurotoxin has revolutionized the treatment of spasticity and is now administered worldwide. There are currently three leading botulinum neurotoxin type A products available in the Western Hemisphere: onabotulinum toxin-A (ONA) Botox(?), abobotulinum toxin-A (ABO), Dysport(?), and incobotulinum toxin A (INCO, Xeomin(?)). Although the efficacies are similar, there is an intense debate regarding the comparability of various preparations. Here we will address the clinical issues of potency and conversion ratios, as well as safety issues such as toxin spread and immunogenicity, to provide guidance for BoNT-A use in clinical practice. INCO was shown to be as effective as ONA with a comparable adverse event profile when a clinical conversion ratio of 1:1 was used. The available clinical and preclinical data suggest that a conversion ratio ABO:ONA of 3:1-or even lower-could be appropriate for treating spasticity, cervical dystonia, and blepharospasm or hemifacial spasm. A higher conversion ratio may lead to an overdosing of ABO. While uncommon, distant spread may occur; however, several factors other than the pharmaceutical preparation are thought to affect spread. Finally, whereas the three products have similar efficacy when properly dosed, ABO has a better cost-efficacy profile.

From Poison to Promise: The Evolution of Tetrodotoxin and Its Potential as a Therapeutic

Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a poison and for its lethal effects on humans when ingested, TTX is primarily a powerful sodium channel inhibitor that targets voltage-gated sodium channels, including six of the nine mammalian isoforms. Although lethal doses for humans range from 1.5-2.0 mg TTX (blood level 9 ng/mL), when it is administered at levels far below LD₅₀, TTX exhibits therapeutic properties, especially to treat cancer-related pain, neuropathic pain, and visceral pain. Furthermore, TTX can potentially treat a variety of medical ailments, including heroin and cocaine withdrawal symptoms, spinal cord injuries, brain trauma, and some kinds of tumors. Here, we (i) describe the perplexing evolution and ecology of tetrodotoxin, (ii) review its mechanisms and modes of action, and (iii) offer an overview of the numerous ways it may be applied as a therapeutic. There is much to be explored in these three areas, and we offer ideas for future research that combine evolutionary biology with therapeutics. The TTX system holds great promise as a therapeutic and understanding the origin and chemical ecology of TTX as a poison will only improve its general benefit to humanity.

LMK235, a small molecule inhibitor of HDAC4/5, protects dopaminergic neurons against neurotoxin- and α-synuclein-induced degeneration in cellular models of Parkinson's disease

Epigenetic modifications in neurodegenerative disease are under investigation for their roles in disease progression. Alterations in acetylation rates of certain Parkinson's disease (PD)-linked genes have been associated with the pathological progression of this disorder. In light of this, and given the lack of disease-modifying therapies for PD, HDAC inhibitors (HDIs) are under consideration as potential pharmacological agents. The neuroprotective effects of pan-HDACs and some class-specific inhibitors have been tested in in vivo and in vitro models of PD, with varying outcomes. Here we used gene co-expression analysis to identify HDACs that are associated with human dopaminergic (DA) neuron development. We identified HDAC3, HDAC5, HDAC6 and HDAC9 as being highly correlated with the DA markers, SLC6A3 and NR4A2. RT-qPCR revealed that mRNA expression of these HDACs exhibited similar temporal profiles during embryonic mouse midbrain DA (mDA) neuron development. We tested the neuroprotective potential of a number of class-specific small molecule HDIs on human SH-SY5Y cells, using neurite growth as a phenotypic readout of neurotrophic action. Neither the class I-specific HDIs, RGFP109 and RGFP966, nor the HDAC6 inhibitor ACY1215, had significant effects on neurite outgrowth. However, the class IIa HDI, LMK235 (a HDAC4/5 inhibitor), significantly increased histone acetylation and neurite outgrowth. We found that LMK235 increased BMP-Smad-dependent transcription in SH-SY5Y cells and that this was required for its neurite growth-promoting effects on SH-SY5Y cells and on DA neurons in primary cultures of embryonic day (E) 14 rat ventral mesencephalon (VM). These effects were also seen in SH-SY5Y cells transfected with HDAC5 siRNA. Furthermore, LMK235 treatment exerted neuroprotective effects against degeneration induced by the DA neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺), in both SH-SY5Y cells and cultured DA neurons. Treatment with LMK235 was also neuroprotective against axonal degeneration induced by overexpression of wild-type (WT) or A53T mutant α-synuclein in both SH-SY5Y cells and primary cultures of DA neurons. In summary, these data show the neuroprotective potential of the class IIa HDI, LMK235, in cell models of relevance to PD.

A cross-over inhibitor of the botulinum neurotoxin light chain B: a natural product implicating an exosite mechanism of action

Clostridium botulinum produces the most lethal toxins known to man, as such they are high risk terrorist threats, and alarmingly there is no approved therapeutic. We report the first cross-over small molecule inhibitor of these neurotoxins and propose a mechanism by which it may impart its inhibitory activity.