Recovery Mimicking “Ideal” CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents

Introduction: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. Methods: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic “ideal” continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. Results: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. Conclusion: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition. (AU)

Recovery Mimicking "Ideal" CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents.

INTRODUCTION: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. METHODS: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic "ideal" continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. RESULTS: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. CONCLUSION: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition.

Cognitive Impairments, Neuroinflammation and Blood-Brain Barrier Permeability in Mice Exposed to Chronic Sleep Fragmentation during the Daylight Period.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-brain barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks and in a subset 2 or 6 weeks of normal sleep recovery. The presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation, as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery (p < 0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patients with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite the normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

Solriamfetol enhances wakefulness and improves cognition and anxiety in a murine model of OSA.

BACKGROUND: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH). Excessive daytime sleepiness (EDS) is a common consequence of OSA and is associated with cognitive deficits and anxiety. Modafinil (MOD) and Solriamfetol (SOL) are potent wake-promoting agents clinically used to improve wakefulness in OSA patients with EDS. METHODS: Male C57Bl/6J mice were exposed to either IH or room air (RA) controls during the light phase for 16 weeks. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg) or vehicle (VEH) for 9 days while continuing IH exposures. Sleep/wake activity was assessed during the dark (active) phase. Novel object recognition (NOR), elevated-plus maze test (EPMT), and forced swim test (FST) were performed before and after drug treatment. RESULTS: IH exposure increased dark phase sleep percentage and reduced wake bouts lengths and induced cognitive deficits and anxiogenic effects. Both SOL and MOD treatments decreased sleep propensity under IH conditions, but only SOL promoted improvements in NOR performance (explicit memory) and reduced anxiety-like behaviors. CONCLUSION: Chronic IH, a hallmark feature of OSA, induces EDS in young adult mice that is ameliorated by both SOL and MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits and promotes anxiolytic effects. Thus, SOL could potentially benefit OSA patients beyond EDS management.

Solriamfetol improves chronic sleep fragmentation-induced increases in sleep propensity and ameliorates explicit memory in male mice.

Obstructive sleep apnea (OSA) is a highly prevalent condition characterized by episodes of partial or complete breath cessation during sleep that induces sleep fragmentation (SF). One of the frequent manifestations of OSA is the presence of excessive daytime sleepiness (EDS) associated with cognitive deficits. Solriamfetol (SOL) and modafinil (MOD) are wake-promoting agents commonly prescribed to improve wakefulness in OSA patients with EDS. This study aimed to assess the effects of SOL and MOD in a murine model of OSA characterized by periodic SF. Male C57Bl/6J mice were exposed to either control sleep (SC) or SF (mimicking OSA) during the light period (06:00 h to 18:00 h) for 4 weeks, which consistently induces sustained excessive sleepiness during the dark phase. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg), or vehicle for 1 week while continuing exposures to SF or SC. Sleep/wake activity and sleep propensity were assessed during the dark phase. Novel Object Recognition test, Elevated-Plus Maze Test, and Forced Swim Test were performed before and after treatment. SOL or MOD decreased sleep propensity in SF, but only SOL induced improvements in explicit memory, while MOD exhibited increased anxiety behaviors. Chronic SF, a major hallmark of OSA, induces EDS in young adult mice that is mitigated by both SOL and MOD. SOL, but not MOD, significantly improves SF-induced cognitive deficits. Increased anxiety behaviors are apparent in MOD-treated mice. Further studies aiming to elucidate the beneficial cognitive effects of SOL are warranted.

Explicit memory, anxiety and depressive like behavior in mice exposed to chronic intermittent hypoxia, sleep fragmentation, or both during the daylight period.

Obstructive sleep apnea (OSA) is a chronic and highly prevalent condition characterized by chronic intermittent hypoxia (IH) and sleep fragmentation (SF), and can lead to a vast array of end-organ morbidities, particularly affecting cardiovascular, metabolic and neurobehavioral functioning. OSA can induce cognitive and behavioral and mood deficits. Male C57Bl/6J 8-week-old mice were housed in custom-designed cages with a silent motorized mechanical sweeper traversing the cage floor at 2-min intervals (SF) during daylight for four weeks. Sleep control (SC) consisted of keeping sweeper immobile. IH consisted of cycling FiO2 21% 90 seconds-6.3% 90s or room air (RA; FiO2 21%) for sixteen weeks and combined SF-IH was conducted for nine weeks. Open field novel object recognition (NOR) testing, elevated-plus maze test (EPMT), and forced swimming test (FST) were performed. SF induced cognitive NOR performance impairments in mice along with reduced anxiety behaviors while IH induced deficits in NOR performance, but increased anxiety behaviors. SF-IH induced impaired performance in NOR test of similar magnitude to IH or SF alone. Combined SF-IH exposures did not affect anxiety behaviors. Thus, both SF an IH altered cognitive function while imposing opposite effects on anxiety behaviors. SF-IH did not magnify the detrimental effects of isolated SF or IH and canceled out the effects on anxiety. Based on these findings, the underlying pathophysiologic processes underlying IH and SF adverse effects on cognitive function appear to differ, while those affecting anxiety counteract each other.