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Dexpramipexole Enhances K+ Currents and Inhibits Cell Excitability in the Rat Hippocampus In Vitro

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Abstract

Dexpramipexole (DEX) has been described as the first-in-class F1Fo ATP synthase activator able to boost mitochondrial bioenergetics and provide neuroprotection in experimental models of ischemic brain injury. Although DEX failed in a phase III trial in patients with amyotrophic lateral sclerosis, it showed favorable safety and tolerability profiles. Recently, DEX emerged as a Nav1.8 Na+ channel and transient outward K+ (IA) conductance blocker, revealing therefore an unexpected, pleiotypic pharmacodynamic profile. In this study, we performed electrophysiological experiments in vitro aimed to better characterize the impact of DEX on voltage-dependent currents and synaptic transmission in the hippocampus. By means of patch-clamp recordings on isolated hippocampal neurons, we found that DEX increases outward K+ currents evoked by a voltage ramp protocol. This effect is prevented by the non-selective voltage-dependent K+ channel (Kv) blocker TEA and by the selective small-conductance Ca2+-activated K+ (SK) channel blocker apamin. In keeping with this, extracellular field recordings from rat hippocampal slices also demonstrated that the compound inhibits synaptic transmission and CA1 neuron excitability. Overall, these data further our understanding on the pharmacodynamics of DEX and disclose an additional mechanism that could underlie its neuroprotective properties. Also, they identify DEX as a lead to develop new modulators of K+ conductances.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

The present work was supported by the University of Florence (Fondi Ateneo), by grants from Italian Foundation for Multiple Sclerosis (FISM) (2019/R-Single/036 (AMP and EC) and 2014/R/6 (AC)); by Fondazione Umberto Veronesi (EC), by PRIN 2017 (AC), Regione Toscana Progetto Salute 2018 (AC), AIRC, and Fondazione CR Firenze under IG 2017 - ID. 2045 (AC).

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Authors and Affiliations

  1. Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

    Elisabetta Coppi, Federica Cherchi, Martina Venturini & Anna Maria Pugliese

  2. Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy

    Daniela Buonvicino, Giuseppe Ranieri & Alberto Chiarugi

Authors
  1. Elisabetta Coppi
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  2. Daniela Buonvicino
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  3. Giuseppe Ranieri
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  4. Federica Cherchi
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  5. Martina Venturini
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  6. Anna Maria Pugliese
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  7. Alberto Chiarugi
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Contributions

EC and AC made substantial contributions to the conception or design of the work; EC, DB, GR, FC, and MV performed the experiments and analyzed data; EC, AMP, and AC worked on interpretation of data. EC drafted the work; AC and AMP revised it critically; AC approved the version to be published.

Corresponding author

Correspondence to Elisabetta Coppi.

Ethics declarations

The present research does not involve human participants. All animal procedures were conducted according to the Italian Guidelines for Animal Care, DL 26/2014, and authorized by the Italian Ministry of Health, Aut. N. 788/2016-PR.

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Coppi, E., Buonvicino, D., Ranieri, G. et al. Dexpramipexole Enhances K+ Currents and Inhibits Cell Excitability in the Rat Hippocampus In Vitro. Mol Neurobiol 58, 2955–2962 (2021). https://doi.org/10.1007/s12035-021-02300-5

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  • DOI: https://doi.org/10.1007/s12035-021-02300-5

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