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Cyclothiazide-induced persistent increase in respiratory-related activity in vitro
Walter E Babiec1, Kym F Faull, Jack L Feldman
1Department of Physiology, David Geffen School of Medicine, UCLA, Box 951751, C8-161 NPI, Los Angeles,CA 90095-1751, USA. babiec@ucla.edu
The Journal of Physiology
|July 4, 2012
Summary
Cyclothiazide (CTZ) significantly enhances genioglossal motoneuronal activity, offering potential treatments for sleep apnea. This drug-induced potentiation of AMPA-mediated drive to hypoglossal motoneurons provides a lasting increase in airway patency signals.
Area of Science:
- Neuroscience
- Respiratory Physiology
Background:
- Hypoglossal (XII) motoneurons control genioglossus muscle, crucial for airway patency during sleep.
- Upper airway motor disorders like obstructive sleep apnea need novel therapeutic targets.
- Enhancing AMPA-mediated drive to XII motoneurons is a potential therapeutic strategy.
Purpose of the Study:
- To investigate the effects of cyclothiazide (CTZ) on hypoglossal motoneuronal excitability.
- To determine if CTZ can induce long-lasting potentiation of respiratory-related XII nerve activity.
- To explore the mechanisms underlying CTZ-induced facilitation.
Main Methods:
- Rhythmically active neonatal rat medullary slices were used.
- Cyclothiazide (CTZ) was applied to slices.
- Respiratory-related XII nerve activity was recorded and analyzed.
- Miniature excitatory postsynaptic currents (mEPSCs) and mass spectrometry were employed.
Main Results:
- CTZ treatment profoundly and lastingly increased XII nerve burst amplitude (262% of control).
- Facilitation persisted for at least 12 hours post-treatment.
- Increased endogenous AMPA-mediated drive currents to XII motoneurons were observed.
- The effect was not dependent on receptor activation or kinase activity, but on CTZ bioavailability.
Conclusions:
- Cyclothiazide induces a long-lasting potentiation of inspiratory drive to XII motoneurons.
- This effect is mediated by prolonged CTZ bioavailability, not synaptic plasticity.
- These findings suggest a potential therapeutic approach for upper airway motor deficits.
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