Overview of Ion Channels, Antiepileptic Drugs, and Seizures
Carl L. Faingold, Gerhard H. Fromm in Drugs for Control of Epilepsy:, 2019
Potassium channels are ubiquitous in eukaryotic cells and exhibit more diverse characteristics than channels for other ions.22 Over a dozen types of K+ channels have already been identified using variations on the patch clamp technique.2 Selective toxins also have been discovered that potently block particular types of K+ channels, which allow examination of the role of the particular current type in controlling the excitability pattern of specific cell types.23 These agents include apamin, a toxin from the honey bee, that inhibits Ca2+-activated K+ channels. Two scorpion toxins, charybdotoxin and noxioustoxin, and a toxin from mamba snake venom, dendrotoxin, also selectively affect different K+ channels.23 G-proteins act to couple many types of K+ channel to neurotransmitters.24
Neuropeptide Receptor-Ion Channel Coupling in the Mammalian Brain
Gerard O’Cuinn in Metabolism of Brain Peptides, 2020
Voltage-clamp experiments in brain slice preparations have revealed that activation of the CCKA receptor reduces a potassium current to excite raphe neurones28. The potassium current involved is not dependent on extracellular calcium, since the inward current produced by CCK was not affected by removal of calcium ions or by the calcium-dependent channel blockers, charybdotoxin (100nM) and apamin (100nM). The response was unaffected by blockers of IA(dendrotoxin 100–300nM) or inward rectifier currents (rubidium, 5mM; cesium, 2mM) but was blocked by barium (1–2mM).
In vitro discovery of a human monoclonal antibody that neutralizes lethality of cobra snake venom
Published in mAbs, 2022
Line Ledsgaard, Andreas H. Laustsen, Urska Pus, Jack Wade, Pedro Villar, Kim Boddum, Peter Slavny, Edward W. Masters, Ana S. Arias, Saioa Oscoz, Daniel T. Griffiths, Alice M. Luther, Majken Lindholm, Rachael A. Leah, Marie Sofie Møller, Hanif Ali, John McCafferty, Bruno Lomonte, José M. Gutiérrez, Aneesh Karatt-Vellatt
Previously, we described the discovery of an oligoclonal mixture of human antibodies capable of neutralizing dendrotoxin-mediated neurotoxicity of black mamba venom in a rodent model.19 Although the cocktail of antibodies tested in that study did neutralize whole venom, the model, using intracerebroventricular injection (i.c.v.), did not account for the effects elicited by α-neurotoxins, since their main target is the nAChR in the neuromuscular junctions. Thus, the i.c.v. model is not as clinically relevant as i.v. injection, which is recommended by WHO as the standard for assessing antivenoms. Another study has reported in vivo neutralization of α-cobratoxin-induced lethality by a VHH and a VHH2-Fc following intraperitoneal injection in mice.23 However, to date, no study has successfully demonstrated the neutralization of lethality caused by a whole venom (or a purified toxin) preincubated with a recombinant human monoclonal IgG antibody following i.v. injection.
How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?
Published in Expert Opinion on Drug Discovery, 2019
Animal envenomings are currently still treated using polyclonal antibodies derived from the plasma of hyper-immunized animals (horses, sheep, donkeys, and occasionally rabbits) [12,13,79,90]. When properly manufactured, these life-saving medicines are effective in neutralizing animal venoms. However, due to their heterologous nature, they have a propensity to cause immunological reactions in human recipients [90]. To circumvent this challenge of immunogenicity, and to improve other therapeutic properties, such as enhancing efficacy and reducing batch-to-batch variation, researchers worldwide have started to embrace different antibody technologies with the goal of developing recombinant antivenoms [89,91,92]. Recently, the discovery of the first fully human oligoclonal IgGs against animal toxins was reported [93]. Here, it was demonstrated that phage display selection employing naïve human antibody libraries could be exploited to discover mixtures of human monoclonal IgGs that could abrogate dendrotoxin-mediated neurotoxicity of black mamba (Dendroaspis polylepis) whole venom in vivo [93]. Also, other researchers have recently reported the discovery of human monoclonal scFvs that can broadly neutralize toxins from multiple scorpion species [94,95], as well as it has been shown that experimental antivenoms based on nanobodies and nanobody-constructs can be used to effectively neutralize snake toxins and venoms [96,97]. These and other recent results in antibody discovery within animal envenomings [90,98] (Figure 4) now warrant further development efforts within envenoming therapy. However, the path towards the approval and marketing of fundamentally novel antivenom products is likely to be long, complicated, and require significant support and international collaboration [14,84], as the field of next-generation envenoming therapeutics is still in its infancy.
Related Knowledge Centers
- Mamba
- Neuromuscular Junction
- Neurotoxin
- Potassium Channel
- Protein
- Ion Channel
- Acetylcholine
- Voltage-Gated Ion Channel
- Neuron
- Pharmacology