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Dexpramipexole Enhances K+ Currents and Inhibits Cell Excitability in the Rat Hippocampus In Vitro
- Source :
- Molecular Neurobiology. 58:2955-2962
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
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.
- Subjects :
- 0301 basic medicine
Chemistry
Neuroscience (miscellaneous)
Hippocampal neurons
K
+
channels
Neuronal excitability
Population spike
Synaptic transmission
Hippocampal formation
Neurotransmission
Apamin
Neuroprotection
03 medical and health sciences
Cellular and Molecular Neuroscience
Electrophysiology
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
Neurology
Biophysics
medicine
Channel blocker
Dexpramipexole
hormones, hormone substitutes, and hormone antagonists
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 15591182 and 08937648
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Molecular Neurobiology
- Accession number :
- edsair.doi.dedup.....06c7007a7847f74bfc85906fce89da5c