Hypocretin (orexin) cell loss in Parkinson's disease

Abstract

It has recently been reported that Parkinson's disease (PD) is preceded and accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep behaviour disorder, hallucinations and depression, symptoms which are frequently as troublesome as the motor symptoms of PD. All these symptoms are present in narcolepsy, which is linked to a selective loss of hypocretin (Hcrt) neurons. In this study, the Hcrt system was examined to determine if Hcrt cells are damaged in PD. The hypothalamus of 11 PD (mean age 79 +/- 4) and 5 normal (mean age 77 +/- 3) brains was examined. Sections were immunostained for Hcrt-1, melanin concentrating hormone (MCH) and alpha synuclein and glial fibrillary acidic protein (GFAP). The substantia nigra of 10 PD brains and 7 normal brains were used for a study of neuromelanin pigmented cell loss. The severity of PD was assessed using the Hoehn and Yahr scale and the level of neuropathology was assessed using the Braak staging criteria. Cell number, distribution and size were determined with stereologic techniques on a one in eight series. We found an increasing loss of hypocretin cells with disease progression. Similarly, there was an increased loss of MCH cells with disease severity. Hcrt and MCH cells were lost throughout the anterior to posterior extent of their hypothalamic distributions. The percentage loss of Hcrt cells was minimal in stage I (23%) and was maximal in stage V (62%). Similarly, the percentage loss of MCH cells was lowest in stage I (12%) and was highest in stage V (74%). There was a significant increase (P = 0.0006, t = 4.25, df = 15) in the size of neuromelanin containing cells in PD patients, but no difference in the size of surviving Hcrt (P = 0.18, t = 1.39, df = 14) and MCH (P = 0.28, t = 1.39, df = 14) cells relative to controls. In summary, we found that PD is characterized by a massive loss of Hcrt neurons. Thus, the loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of PD and may be ameliorated by treatments aimed at reversing the Hcrt deficit. We also saw a substantial loss of hypothalamic MCH neurons. The losses of Hcrt and MCH neurons are significantly correlated with the clinical stage of PD, not disease duration, whereas the loss of neuromelanin cells is significantly correlated only with disease duration. The significant correlations that we found between the loss of Hcrt and MCH neurons and the clinical stage of PD, in contrast to the lack of a relationship of similar strength between loss of neuromelanin containing cells and the clinical symptoms of PD, suggests a previously unappreciated relationship between hypothalamic dysfunction and the time course of the overall clinical picture of PD.

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.…”