Peripheral Administration of the Kv1.3-Blocking Peptide HsTX1[R14A] Improves Cognitive Performance in Senescence Accelerated SAMP8 Mice.

Autor: Pan Y; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia.; Department of Organ Anatomy, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, 980-8575, Japan., Kagawa Y; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.; Department of Organ Anatomy, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, 980-8575, Japan., Sun J; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia., Lucas DSD; Monash Bioinformatics Platform, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia., Takechi R; School of Biomedical Sciences, Curtin University, Bentley, WA, 6102, Australia.; School of Public Health, Curtin University, Bentley, WA, 6102, Australia., Mamo JCL; School of Biomedical Sciences, Curtin University, Bentley, WA, 6102, Australia.; School of Public Health, Curtin University, Bentley, WA, 6102, Australia., Wai DCC; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia., Norton RS; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.; ARC Centre for Fragment-Based Design, Monash University, Parkville, VIC, 3052, Australia., Jin L; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia. liang.jin@unimelb.edu.au., Nicolazzo JA; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. joseph.nicolazzo@monash.edu.
Jazyk: angličtina
Zdroj: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2023 Jul; Vol. 20 (4), pp. 1198-1214. Date of Electronic Publication: 2023 May 24.
DOI: 10.1007/s13311-023-01387-z
Abstrakt: Increased expression of the voltage-gated potassium channel Kv1.3 in activated microglia, and the subsequent release of pro-inflammatory mediators, are closely associated with the progression of Alzheimer's disease (AD). Studies have shown that reducing neuroinflammation through the non-selective blockade of microglial Kv1.3 has the potential to improve cognitive function in mouse models of familial AD. We have previously demonstrated that a potent and highly-selective peptide blocker of Kv1.3, HsTX1[R14A], not only entered the brain parenchyma after peripheral administration in a lipopolysaccharide (LPS)-induced mouse model of inflammation, but also significantly reduced pro-inflammatory mediator release from activated microglia. In this study, we show that microglial expression of Kv1.3 is increased in senescence accelerated mice (SAMP8), an animal model of sporadic AD, and that subcutaneous dosing of HsTX1[R14A] (1 mg/kg) every other day for 8 weeks provided a robust improvement in cognitive deficits in SAMP8 mice. The effect of HsTX1[R14A] on the whole brain was assessed using transcriptomics, which revealed that the expression of genes associated with inflammation, neuron differentiation, synapse function, learning and memory were altered by HsTX1[R14A] treatment. Further study is required to investigate whether these changes are downstream effects of microglial Kv1.3 blockade or a result of alternative mechanisms, including any potential effect of Kv1.3 blockade on other brain cell types. Nonetheless, these results collectively demonstrate the cognitive benefits of Kv1.3 blockade with HsTX1[R14A] in a mouse model of sporadic AD, demonstrating its potential as a therapeutic candidate for this neurodegenerative disease.
(© 2023. The Author(s).)
Databáze: MEDLINE
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