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Screening effects of HCN channel blockers on sleep/wake behavior in zebrafish

Fusun Doldur-Balli1, Sandra P Smieszek2, Brendan T Keenan1

  • 1Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Frontiers in Neuroscience
|April 3, 2024
PubMed

Insights

Three hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers were tested on zebrafish larvae. Results show Ivabradine, Zatebradine Hydrochloride, and ZD7288 impact sleep latency, daytime activity, and nighttime sleep duration.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are crucial for electrical rhythmicity in the heart, retina, and brain.
  • Ivabradine, an FDA-approved HCN channel blocker, reduces heart rate by inhibiting sinoatrial node activity.
  • Emerging evidence links HCN channels to the regulation of sleep-wake cycles.

Purpose of the Study:

  • To investigate the effects of three HCN channel blockers (Ivabradine, Zatebradine Hydrochloride, ZD7288) on sleep-wake behavior in zebrafish larvae.
  • To determine dose-dependent impacts of these blockers on specific sleep and activity parameters.

Main Methods:

  • Utilized zebrafish larvae as a model organism for high-throughput behavioral phenotyping.
  • Administered varying doses of Ivabradine, Zatebradine Hydrochloride, and ZD7288.
  • Analyzed sleep latency, daytime activity, and nighttime sleep duration using statistical methods (ANOVA).

Main Results:

  • Ivabradine (0.1 μM) significantly shortened the latency to daytime sleep (p=0.02).
  • Zatebradine Hydrochloride (30 μM) moderately reduced average daytime activity (p=0.024).
  • ZD7288 (4.5 μM) increased nighttime sleep duration (p=0.036).

Conclusions:

  • Different HCN channel antagonists differentially affect distinct parameters of sleep and activity.
  • These findings highlight the role of HCN channels in regulating complex behaviors like sleep.
  • Zebrafish larvae serve as a valuable model for studying the behavioral pharmacology of HCN channel modulators.
Keywords:
HCN channel blockerIvabradine (Corlanor)ZD7288Zatebradine hydrochloridedrug screeningsleep/wakezebrafish

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