The activation of microglia and their subsequent release of pro-inflammatory mediators in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases are associated with increased microglial expression of the voltage-gated potassium channel Kv1.3.1 Analogues of the sea anemone peptide ShK (ShK-186) and the scorpion peptide HsTX1 (HsTX1[R14A]) are potent and selective blockers of this channel that have already proven to be efficacious in animal models of autoimmune diseases such as psoriasis, rheumatoid arthritis and multiple sclerosis.2-4 While these peptides would be excluded from the CNS in healthy subjects by the blood-brain barrier (BBB), there is strong evidence that the integrity of the BBB is compromised in neuroinflammatory diseases. Indeed, we have shown that, in mice treated with lipopolysaccharide (LPS) as a model of neuroinflammation, subcutaneously administered HsTX1[R14A] was detectable in the brain at appreciable levels within an hour after dosing.5 In this mouse model of LPS-induced neuroinflammation, both immediate and delayed subcutaneous doses of HsTX1[R14A] (2 mg/kg) significantly reduced both plasma and brain levels of the pro-inflammatory mediators TNF-α, IL-1β and IL-6, with no impact on the anti-inflammatory IL-10. In further experiments in a mouse model of sporadic Alzheimer’s disease, cognitive benefits of HsTX1[R14A] are evident. The high chemical and proteolytic stability of HsTX1[R14A], its long pharmacodynamic half-life (as assessed in animal models of autoimmune diseases) and its ability to enter the brain in neuroinflammatory conditions combine to make HsTX1[R14A] an attractive candidate for the treatment of diseases with a neuroinflammatory component.
1 Tajti, G. et al. Biochem. Pharmacol. 181, 114146 (2020)
2 Chandy, K. G. & Norton, R. S. Curr. Opin. Chem. Biol. 38, 97-107 (2017)
3 Tarcha, E. J. et al. PloS One 12, e0180762 (2017)
4 Rashid, M. H. et al. Sci Rep 4, 4509 (2014)
5 Reddiar, S. B. et al. Toxicon 195, 29-36 (2021)