The orexin agonist ROXA-43 enhances cortical gamma power and motor function in a mouse model of Parkinson’s disease

The neuropeptide orexin (OX) regulates wakefulness, energy balance, muscle tone, spontaneous physical activity (SPA) and other physiological processes. The OX-neurons project to the basal ganglia and the thalamus, which are involved in sensorimotor processes. Recent studies in patients with Parkinson's disease (PD) and animal models of PD showed a loss of OX neurons and slowing of sensorimotor oscillatory activity (SMOA), specifically increased beta power. Previously we showed that central administration of OX alters SMOA, by enhancing power in the gamma band, decreasing beta power, and priming the brain for motor activity in rats. This altered oscillatory activity was associated with increased SPA and muscle tone. Priming the motor system for movement using OX would be a novel and promising therapeutic approach to mitigate the motor symptoms of PD. Peripherally administrable small molecule OX agonists are now available. Similar to the effect of exogenous OX on SPA and sleep, such OX agonists (e.g. ROXA-47 and ROXA-43) enhance SPA. Given that OXA promotes motor preparedness, and PD is associated with OXA neuron loss, we hypothesized that peripherally administered OX agonists restore SMOA, and improve motor function in the 3K mouse model of PD. To test our hypothesis, 12-mo old, male wild type and 3K mice were implanted with a radiotelemetric transmitter and EEG/EMG electrodes. Following surgical recovery, we recorded the SMOA after peripheral administration of either the OX agonist (ROXA-43 30mg/kg, IP) or vehicle. The SMOA was recorded during 60 min post-injection. We scored the vigilance states (Awake, REM Sleep, Slow-Wave Sleep) in 10 sec epochs, and computed the fast Fourier transform (FFT) of the EEG signal. Data were evaluated based on the effect of disease state and treatment using Cohen’s d effect size. An effect size >= 0.5 is considered moderate, whereas an effect size >= 0.8 is considered large. Results showed that male 3K mice have significantly less wake time than WT mice (effect size=-0.943), and that the OX agonist ROXA-43 increased the wake time of 3K mice (effect size=1.705). Power spectra analysis showed that the 3K mice had greater EEG power activity in the high-beta and low-gamma frequencies (20-60Hz) than WT mice, a pathophysiological marker of PD. The orexin agonist ROXA-43 decreased power in the high-beta and low-gamma range (20-60Hz), and increased it in the high gamma range ( >70 Hz). Previously, we found that SPA was significantly lower in 3K mice and that peripheral administration of the OX agonist ROXA-43 improved SPA in these mice. These results suggest that peripheral administration of OX agonist improves SMOA and motor function in the 3K mice. Importantly, in other PD models the orexin receptors remain intact. This provides a therapeutic target for reduced OX function in PD. These results suggest that targeting OXA pathways with small molecule agonists is of potential therapeutic interest to treat PD and other neurodegenerative diseases characterized by low OX tone. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.