Animal Models of Narcolepsy

Chen, Lichao; Brown, Ritchie E.; Mckenna, James T; McCarley, Robert W.

doi:10.2174/187152709788921717

Cited by 28 publications

(16 citation statements)

References 158 publications

(175 reference statements)

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“…However, even at the highest dose the antagonist did not lead to drop attacks or cataplexy, features observed in the genetic knock out of preproorexin or by destruction of orexin containing neurons in the hypothalamus (Chen et al, 2009; Scammell et al, 2009; Yamauchi et al, 2010). …”

Section: Discussionmentioning

confidence: 96%

Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

Moore

Akladious

et al. 2014

Respiratory Physiology & Neurobiology

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Background The hypothesis was that an orexin 2 receptor (OX2R) agonist would prevent sleep-related disordered breathing. Methods In C57BL/6J (B6) mice, body plethysmography was performed with and without EEG monitoring of state (wakefulness, NREM and REM sleep). Outcome was apnea rate/hr during sleep-wake states at baseline and with an intracerebroventricular administration of vehicle, 4nMol of agonist OBDL, and 4nMol of an antagonist, TCS OX2 29. Results A significant reduction (p=0.035; f=2.99) in apneas/hour occurred, especially with the agonist. Expressed as a function of the change from baseline, there was a significant difference among groups in Wake (p=0.03, f=3.8), NREM (p=0.003, f= 6.98) and REM (p=0.03, f= 3.92) with the agonist reducing the rate of apneas during sleep from 29.7± 4.7 (M+/− SEM) to 7.3±2.4 during sleep (p=0.001). There was also a reduction in apneas during wakefulness. Administration of the antagonist did not increase event rate over baseline levels. Conclusions The B6 mouse is a preclinical model of wake-and sleep-disordered breathing, and the orexin receptor agonist at a dose of 4nMol given intracerebroventricularly will reduce events in sleep and also wakefulness.

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Section: Discussionmentioning

confidence: 96%

Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

Moore

Akladious

et al. 2014

Respiratory Physiology & Neurobiology

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“…Sleep disruption is a common symptom of several central nervous system disorders, and is associated with abnormal orexin function (Dauvilliers et al, 2003). While the strongest evidence supporting the role of orexin in sleep are data showing that the sleep disorder narcolepsy is caused by disrupted orexin signaling (Chemelli et al, 1999; Chen et al, 2009; Nishino et al, 2000), it is unclear how orexin contributes to other disorders of sleep and wakefulness. Mechanistic studies in rodent models can elucidate the association between altered orexin function and sleep disorders.…”

Section: Animal Modelsmentioning

confidence: 99%

Sleep disorders, obesity, and aging: The role of orexin

Nixon

Mavanji

Butterick

et al. 2015

Ageing Research Reviews

109

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The hypothalamic neuropeptides orexin A and B (hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of orexin signaling has been linked to narcolepsy, obesity, and age-related disorders. In this review, we present an overview of our current understanding of orexin function, focusing on sleep disorders, energy balance, and aging, in both rodents and humans. We first discuss animal models used in studies of obesity and sleep, including loss of function using transgenic or viral-mediated approaches, gain of function models using exogenous delivery of orexin receptor agonist, and naturally-occurring models in which orexin responsiveness varies by individual. We next explore rodent models of orexin in aging, presenting evidence that orexin loss contributes to age-related changes in sleep and energy balance. In the next section, we focus on clinical importance of orexin in human obesity, sleep, and aging. We include discussion of orexin loss in narcolepsy and potential importance of orexin in insomnia, correlations between animal and human studies of age-related decline, and evidence for orexin involvement in age-related changes in cognitive performance. Finally, we present a summary of recent studies of orexin in neurodegenerative disease. We conclude that orexin acts as an integrative homeostatic signal influencing numerous brain regions, and that this pivotal role results in potential dysregulation of multiple physiological processes when orexin signaling is disrupted or lost.

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“…Many neurological diseases can be found in non-human mammals (9–12) both acquired and hereditary (such as myelopathy, brain tumors, epilepsy, muscular dystrophy, and narcolepsy, to mention a few). However, Alzheimer disease and PD are considered specific to Homo sapiens (13–15).…”

Section: Pd Is Specifically Humanmentioning

confidence: 99%

Parkinson Disease: An Evolutionary Perspective

Ruiz

Espay

2017

Front. Neurol.

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There are two central premises to this evolutionary view of Parkinson disease (PD). First, PD is a specific human disease. Second, the prevalence of PD has increased over the course of human history. Several lines of evidence may explain why PD appears to be restricted to the human species. The major manifestations of PD are the consequence of degeneration in the dopamine-synthesizing neurons of the mesostriatal neuronal pathway. It is of note the enormous expansion of the human dopamine mesencephalic neurons onto the striatum compared with other mammals. Hence, an evolutionary bottle neck was reached with the expansion of the massive nigrostriatal axonal arborization. This peculiar nigral overload may partly explain the selective fragility of the human dopaminergic mesencephalic neurotransmission and the unique presence of PD in humans. On the other hand, several facts may explain the increasing prevalence of PD over the centuries. The apparently low prevalence of PD before the twentieth century may be related to the shorter life expectancy and survival compared to present times. In addition, changes in lifestyle over the course of human history might also account for the increasing burden of PD. Our hunter-gatherers ancestors invested large energy expenditure on a daily basis, a prototypical physical way of life for which our genome remains adapted. Technological advances have led to a dramatic reduction of physical exercise. Since the brain release of neurotrophic factors (including brain-derived neurotrophic factor) is partially exercise related, the marked reduction in exercise may contribute to the increasing prevalence of PD.

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Animal Models of Narcolepsy

Cited by 28 publications

References 158 publications

Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

Sleep disorders, obesity, and aging: The role of orexin

Parkinson Disease: An Evolutionary Perspective

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