By Luigi Taranto Montemurro, MD, CSO of Apnimed and David P. White, MD, SVP Medical Affairs, Apnimed
Research has shown that patients with obstructive sleep apnea (OSA) share the anatomical disadvantage of a narrow upper airway that is prone to collapse during sleep. In our previous article, we described how the identification of three additional traits – upper airway response, arousal threshold and loop gain – in the last 15 years has improved the understanding of OSA pathophysiology. These discoveries also spurred research into the development of pharmaceutical treatment options that potentially could treat OSA by targeting one or more of these traits.
As awareness of the role of the upper airway response in OSA grew, OSA researchers began searching for the specific neurotransmitters involved in the control of the dilator muscles in the upper airway, especially the genioglossus (tongue muscle), during sleep. The idea has been that modulating the right neurotransmitter with a drug potentially could treat OSA by activating the muscles to keep the airway open.
However, the search for the specific neurotransmitter was not straightforward because the nervous system contains at least five or six neurotransmitters systems that are affected by sleep. Each system carries out different functions in the brain – sometimes many and even divergent functions from one cell type to another. These complexities have made it challenging to determine which neurotransmitters regulate the upper airway muscles during sleep.
For example, the neurotransmitter serotonin was an early suspect in OSA. But serotonin interacts with seven different families of receptors in the central nervous system (CNS) and peripheral nervous system, and these interactions can be excitatory or inhibitory depending on the synapses involved. Nevertheless, most data now suggest that decreased activity of serotonergic neurons is not primarily responsible for the reduced activity of the genioglossus during sleep.
Another neurotransmitter system that changes between waking and sleep consists of GABA (gamma-aminobutyric acid) and its receptors. While this system is mainly responsible for the relaxation of skeletal muscles during sleep, it is less involved in the inhibition of activity in upper airway and respiratory muscles.
It takes two (neurotransmitters)
A breakthrough came in 2006 when a rat study conducted by Richard Horner and colleagues at the University of Toronto showed that relaxation of the genioglossus in the transition from wakefulness to non-REM (non-rapid eye movement) sleep was due to decreasing levels of norepinephrine at the hypoglossal motor nucleus which controls genioglossal activity. The study also showed that increasing norepinephrine concentration at this motor nucleus activated the genioglossus during non-REM sleep but failed to do so during REM sleep. This finding suggested another neurotransmitter was responsible for regulating genioglossus activity in REM sleep.
Horner and colleagues conducted additional rat studies in 2013 which showed that muscarinic inhibition was mainly responsible for the loss of genioglossus activity during REM sleep.1 Together, the two sets of findings suggested that OSA potentially could be treated by combining stimulation of the norepinephrine system with a noradrenergic agent and antagonism of muscarinic receptor activity to restore genioglossus activity during non-REM and REM sleep, respectively.
However, research has shown that norepinephrine can promote wakefulness, so stimulating its production to potentially treat OSA requires a delicate balance: increase norepinephrine sufficiently to bring genioglossus activity near to waking levels, but not to a level that sleep would be disturbed. We believe that with a combination therapy this balancing act can be easier to strike if the potential wake-promoting effects of the noradrenergic agent are offset by the potential sedative effects of the muscarinic receptor antagonist.
Apnimed is conducting research designed to target this complex neuromuscular system, with its complex neurobiology, to develop a potential oral treatment for OSA. To achieve this, Apnimed is working to develop different combinations of agents that would potentially stimulate the upper airway muscles, keeping the airway open while keeping the patient asleep and not disturbing other neurobiological systems.
Apnimed is also exploring the development of treatment options to address a low arousal threshold and high loop gain that we believe can also contribute to OSA. This approach to potentially treat OSA aims to address the specific needs of each patient with the convenience of an appropriate oral treatment option.
FOR ADDITIONAL INFORMATION:
 Grace, KP et al. Am J Respir Crit Care Med. 2013;187(3):311-9. doi:10.1164/rccm.201209-1654OC.