Sleep disorders are complex situations and there is a detailed correlation of sleep-wake regulation and clinical conditions. But a few examples can help to combine scientific underlying concepts with everyday clinical scenarios. Since the first definition of the hypocretin-orexin system 20 years ago, a literature has emerged investigating the physiological and pathophysiological role of this system and its drug development potential. Disruption of this system has been associated with pathological sleep-wake states such as insomnia and narcolepsy.
The role of the hypocretin / orexin system in other sleep disorders and sleepiness associated with other neurological disorders has also deserved some research. Recent results suggest that subjects with head injury or encephalitis may have moderately but significantly decreased hypocretin levels. A few selected subjects with Guillain-Barré syndrome, Parkinson’s disease (PD), multiple system atrophy, and other neurodegenerative disorders were also found to have shallow hypocretin levels. Importantly, the central actions of orexin coordinate regions of the central autonomous network and endocrine system to regulate motivated behavior, stress response and energy (glucose) metabolism, these multiple actions of orexin are critical to sustain life.
Given these putative clinical goals, there is ongoing research in the development of selective hypocretin / orexin receptor agonists and antagonists. Recently, suvorexant became the first hypocretin / orexin receptor antagonist approved by the US Food and Drug Administration (FDA) for the treatment of insomnia, and researchers have published many studies on the first hypocretin / orexin agonist with good potency and pharmacological selectivity.
As mentioned earlier, narcolepsy has been associated with changes in orexinergic / hypocretinergic neurons. It is a debilitating neurological condition that affects approximately 1 in 2000 people and is characterized by excessive daytime sleepiness, frequent running with sudden muscle paralysis (cataplectic attacks), and transitions from wakefulness to REM sleep. Human narcolepsy is a genetically complex disease and is environmentally affected. The association of HLA with human narcolepsy suggests that it may have an autoimmune origin. Current treatment strategies are essentially symptomatic and include amphetamine-like stimulants and antidepressants met with unsatisfactory results.
It has been found that dogs with narcolepsy have a mutation in the orexin-2 (hypocretin-2) receptor. Mice lacking orexin peptide or orexin (hypocretin) containing neurons exhibited behavioral and EEG signs of narcolepsy. Human subjects with narcolepsy were found to have a lack or very low levels of hypocretin neurons in the CSF (85-95% reduction in neuron count) and orexin-A. These findings were corroborated by post-mortem examination of the brain tissue of subjects with narcolepsy, which showed large losses of orexin neurons. It is not entirely clear what caused this massive loss of orexin neurons. Conversely, the number of melanin concentrating hormone (MCH) neurons is not reduced, indicating that cell loss is relatively specific for hypocretin neurons.
Idiopathic hypersomnia is characterized by excessive daytime sleepiness without sudden muscular paralysis (cataplectic attacks) or sudden transitions from wakefulness to REM sleep, but with a dopaminergic and general aminergic impairment associated with this condition. Some researchers describe low but detectable hypocretin levels in these patients, while others report normal levels. Besides, post mortem studies are not yet available.
Hypocretin Studies in Neurodegenerative Disorders
Sleep disturbances frequently occur in patients with Parkinson’s disease (PD) and may even preclude motor symptoms, thereby demonstrating a close relationship at the central level between autonomic (non-motor symptoms) and sleep centers. Excessive daytime sleepiness has been reported in almost half of PD patients. In post mortem brain studies, hypocretin-1 tissue concentrations in the prefrontal cortex were almost 40% lower in these patients, and the total number of hypocretin neurons was reduced by almost half compared to controls. An MCH neuron loss that increases with disease progression has also been described.
Multiple system atrophy
Seventy percent of patients with multiple system atrophy (MSA), a progressive neurodegenerative disease with undetermined etiology, characterized by Parkinson’s features, cerebellar, autonomic and urogenital dysfunction, and corticospinal disorders. Clinical features include reduced and fragmented sleep, excessive daytime sleepiness, rapid eye movement (REM), sleep behavior disorder (RBD), stridor, and sleep-disordered breathing. In these patients, Benarroch et al. Found up to 70% reduction in total hypocretin neuron count in these patient populations and abundant glial cytoplasmic inclusions in the area of distribution of the hypocretin were identified.
Immune Mediated Neurological Disorders
Guillain-Barré syndrome is a post-infectious polyradiculopathy that mostly affects the peripheral nervous system, often with symptoms of autonomic nervous system failure. Although not uncommon, these patients also show other symptoms of hypothalamic discomfort. Guillain-Barré syndrome is the only disease in which there are consistently undetectable hypocretin levels besides narcolepsy. Patients with the lowest level tend to have a more severe and rapid course of the disease, running with tetraplegia and respiratory failure. The mechanism underlying hypocretin deficiency or very low levels in Guillain-Barré syndrome is unknown, but an immune-mediated hypothalamic dysfunction has been postulated.
Orexin and sleep-related physical disorders: Cardiovascular disease
Almost all body functions are dependent on the autonomic nervous system (ANS) exerting precise control over visceral functions. Sleep disturbance causes increased activity of the sympathetic nervous system associated with high blood pressure, and the risks of hypertension and cardiovascular disease increase as a result of strong acute or prolonged sleep disturbance. The hypocretin / orexin system also contributes to the regulation of cardiovascular functions through the autonomic nervous system. Hypocretin / orexin neurons are reflected in several brain regions involved in the regulation of cardiovascular activity, namely the paraventricular nucleus (PVN), nucleus tractus solitarius and rostral ventrolateral medulla (RVLM), all areas of the central autonomic network.
Overactivation of the hypocretin / orexin system plays a role in the pathogenesis of hypertension. Central administration of orexin A and B has been shown to increase arterial blood pressure and cause tachycardia in animal models. In contrast, orexin / ataxin-3 transgenic rats lacking orexin neurons had significantly reduced sympathetic nervous system tone and lower systolic blood pressure compared to controls. In addition, it has increased levels of hypocretin / orexin in spontaneously hypertensive rats (SHRs).
When blocked by oral administration of almorexant or intracerebroventricular injections of TCSOX229, it did not affect arterial blood pressure in normotensive animals but caused a significant decrease in systolic blood pressure. These data suggest that hypocretin / orexin may play an important role in the pathogenesis of hypertension. In humans, Dauvilliers et al. Reported lower cardiac activation associated with periodic leg movements during sleep in narcoleptic patients. This is suggested to be related to changes in baroreflex sensitivity.
The same group found a large percentage of non-diastolics, and 64% failed to reach the 15% drop point in diastolic blood pressure. Recent data suggest that narcoleptic patients exhibit an increased systolic blood pressure during nighttime REM sleep with a non-decreasing blood pressure pattern at night. Blunted cardiac activation and sleep-related blood pressure reduction in narcoleptic patients may be clinically significant and indicate an increased risk for cardiovascular events potentially attributable to clinically significant hypocretin / orexin deficiency.
In summary, despite being present throughout the animal kingdom, the precise sleep function is still relatively difficult. However, it is clear that sleep regulation is essential for survival, having an important role in these modulating processes through orexin / hypocretin and MCH neurons to the hypothalamus. However, more studies on sleep physiology are needed to determine the internal mechanisms associated with the sleep-wake cycle and their regulatory processes.
Writer: Ozlem Guvenc Agaoglu