Hypocretin (orexin) loss in Parkinson's disease

Abstract

The hypothalamic hypocretin (orexin) system plays a central role in the regulation of various functions, including sleep/wake regulation and metabolism. There is a growing interest in hypocretin function in Parkinson's disease (PD), given the high prevalence of non-motor symptoms such as sleep disturbances in this disorder. However, studies measuring CSF hypocretin levels have yielded contradictory results. In PD patients and matched controls, we (i) estimated the number of hypocretin neurons in post-mortem hypothalami using immunocytochemistry and an image analysis system (ii) quantified hypocretin levels in post-mortem ventricular CSF and (iii) prefrontal cortex using a radioimmunoassay. Furthermore, presence of Lewy bodies was verified in the hypothalamic hypocretin cell area. Data are presented as median (25th-75th percentile). We showed a significant decrease between PD patients and controls in (i) the number of hypocretin neurons (PD: 20 276 (13 821-31 229); controls: 36 842 (32 546-50 938); P = 0.016); (ii) the hypocretin-1 concentration in post-mortem ventricular CSF (PD: 365.5 pg/ml (328.0-448.3); controls: 483.5 (433.5-512.3); P = 0.012) and (iii) the hypocretin-1 concentrations in prefrontal cortex (PD: 389.6 pg/g (249.2-652.2); controls: 676.6 (467.5-883.9); P = 0.043). Hypocretin neurotransmission is affected in PD. The hypocretin-1 concentration in the prefrontal cortex was almost 40% lower in PD patients, while ventricular CSF levels were almost 25% reduced. The total number of hypocretin neurons was almost half compared to controls.

Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates

“…or via nasal spray mist delivery can counteract the effects of sleep deprivation in nonhuman primates and that the intranasal route is more effective. Our findings suggest that intranasal orexin-A administration may be useful in counteracting the effects of sleepiness in sleep-deprived animals and humans, and perhaps in humans with narcolepsy Thannickal et al, 2000) and Parkinson's disease (Fronczek et al, 2007;Thannickal et al, 2007).…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…It is presentlyrecognizedthat early neuronal loss occurs in other regions involved in motor control [58,59] and in neurons of the mesocortical system [60]. The involvement of other neuronal populations takes place later in PD or only in certain clinical phenotypes and includes neuronal loss in the cholinergic basal forebrain [61], in the hypothalamic hypocretin system [62,63] and in the upper brainstem serotonin system [64]. Neuronal loss is very restricted to areas containing LBs, such as the amygdala, the dorsal motor nucleus of the vagus nerve, locus coeruleus and the neocortex [65Ͳ68].…”

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

“…In PD loss of neurons in multiple brain regions paralleling the loss of DA neurons in the SNc occurs (17,32,36,56,121). Two of the cell-specific risk factors standout as common to the other cell types that succumb in PD: autonomous or spontaneous activity with broad action potentials and a depolarized membrane potential that promotes the opening of NMDA receptors.…”