Abstract
Scorpion stings are life threatening in large parts of the world. Toxins from scorpion venom are responsible for severe metabolic and tissue disruption and immunotherapy is the only specific treatment able to neutralize the toxic effects of scorpion venom. The Androctonus mauretanicus (Am) is the most dangerous scorpion in Morocco, whereas in Tunisia Androctonus australis hector (Aah) is causing most casualties. In this work, we investigated the potential of NbF12-10, a new immunotherapeutic concept based on anti-toxin Nanobodies (Nbs) to neutralize Am scorpion venom. We first explored the immune cross-reactivity between Am and Aah scorpions venoms using anti-AahI and anti-AahII polyclonal, NbAahI’F12 (anti-AahI’), monospecific NbAahII10 (anti-AahII) and bispecific NbF12-10 (anti-AahI’/anti- AahII) monoclonal antibodies and subsequently we study the histological damages observed after envenomation with the F3 toxic fraction of Am scorpion venom by intra-cerebroventricular (i.c.v) injection and the capacity of NbF12-10 to reduce tissue damage induced by F3 fraction after i.c.v administration of F3:NbF12-10 mixture, in mice. Results showed significant para-specific activity of anti-Aah polyclonal and monoclonal antibodies towards Am venom fractions. Histological investigations revealed severe tissue damage in brain, lung and liver after i.c.v. administration of F3 fraction. The NbF12-10 pre-mixed with F3 fraction showed an efficient neutralizing capacity against lethal effect of this toxic fraction. Moreover, in vitro pre-incubation of F3 with NbF12-10 at 8-fold molar excess led to significantly reduced tissue damage. Further, NbF12-10 displays a noteworthy potential to neutralize Am toxins and to rescue 50% of envenomed mice from dying. This study provides first evidence that NbF12-10 nano-therapeutic has promising prospective to treat scorpion envenoming in the Maghreb area.
Highlights
Envenoming by stings from dangerous scorpions constitute a frequent medical emergency and an important public health problem in many countries [1,2,3,4,5,6,7,8]
The toxicity of F1, F2 or Gel Filtration Toxic Fraction of Am Venom (F3) fractions was assessed in mice by i.c.v injection of different amounts into Swiss mice
Our results revealed that NbF12-10 ensures the survival of 50 % of mice injected with 35 ng of the F3 fraction with an 8 fold molar excess of Nb (Table 2)
Summary
Envenoming by stings from dangerous scorpions constitute a frequent medical emergency and an important public health problem in many countries [1,2,3,4,5,6,7,8]. The Buthus scorpion genus has the widest spreading throughout the Maghreb Both Am and Aah sub-species are responsible for the majority of stings, especially in children [4,10]. It is well established that the toxicity of scorpion venom is mainly due to the fast diffusion of toxins throughout the body [11,12]. These toxins affect ionic channels (i.e. Na+, K+ Ca2+ or Cl- channels) and modulate the transmission of nervous impulses by increasing the discharge of mediators (catecholamines, cytokines, neuropeptide...) causing the release of metabolic serum biomarkers and tissue damages [1317]. Sodium channel specific toxins are the most represented venom proteins that have been structurally defined and classified in different antigenic groups as identified by polyclonal antibodies. Amm V is one of the most abundant (46% of the whole Amm venom) and active toxin displaying a 75% sequence identity with
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