Blockade of Microglial Kv1.3 Potassium Channels by the Peptide HsTX1[R14A] Attenuates Lipopolysaccharide-mediated Neuroinflammation

The expression of voltage-gated potassium Kv1.3 channels is increased in activated microglia, with nonselective blockade reported to attenuate microglial-mediated neuroinflammation. In this study, we evaluated the impact of a potent and selective peptidic blocker of Kv1.3 channels, HsTX1[R14A], on microglial-mediated neuroinflammation in vitro and in vivo. Treatment with both 0.1 and 1 mg/mL lipopolysaccharide (LPS) significantly (p < 0.05) increased Kv1.3 abundance on the surface of BV-2 microglia in association with increased levels of mRNA for tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The increased transcription of TNF-alpha and IL-6 was significantly attenuated (by 24.9 and 20.2%, respectively) by HsTX1[R14A] (100 nM). The concomitant increase in TNF-alpha and IL-6 release from BV-2 microglia was significantly attenuated by HsTX1[R14A] by 10.7 and 12.6%, respectively. In LPS-treated primary mouse microglia, the levels of TNF-a and nitric oxide were also attenuated by HsTX1[R14A] (26.1 and 20.4%, respectively). In an LPSinduced mouse model of neuroinflammation, both an immediate and delayed subcutaneous dose of HsTX1 [R14A] (2 mg/kg) significantly reduced plasma and brain levels of the pro-inflammatory mediators TNF-alpha, IL 1b and IL-6, with no impact on the anti-inflammatory IL-10. These results demonstrate that HsTX1[R14A] is a promising therapeutic candidate for the treatment of diseases with a neuroinflammatory component. (C) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.