Orexins promote survival of rat cortical neurons

Sokołowska, Paulina; Urbańska, Anna; Namiecińska, Magdalena; Biegańska, Kaja; Zawilska, Jolanta B.

doi:10.1016/j.neulet.2011.11.028

Cited by 34 publications

(29 citation statements)

References 30 publications

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“…Evidence strongly links development of AD and PD with oxidative stress and mitochondrial dysfunction in the brain (Agostinho et al, 2010; Ferreiro et al, 2012; Niranjan, 2013). In recent in vitro and in vivo studies, we and others have shown that orexin is neuroprotective, reducing neuronal damage caused by ischemia or oxidative insult in hypothalamic, hippocampal, and cortical tissue (Butterick et al, 2012; Sokolowska et al, 2012; Yuan et al, 2011). While the mechanism is not fully defined, orexin appears to increase resistance to oxidative stress by upregulation of hypoxia-inducible factor 1 alpha (HIF-1α) (Butterick et al, 2013; Feng et al, 2014; Sikder and Kodadek, 2007; Yuan et al, 2011).…”

Section: Discussionmentioning

confidence: 93%

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

Nixon

Mavanji

Butterick

et al. 2015

Ageing Research Reviews

112

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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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Section: Discussionmentioning

confidence: 93%

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

Nixon

Mavanji

Butterick

et al. 2015

Ageing Research Reviews

112

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“…Intracerebroventricular OxA given during ischaemia induced by middle cerebral artery occlusion promoted neuronal survival [108]; this action is mediated via Ox receptor activation and the PI3K/Akt pathway [92,93]. Given that (i) Ox neurons are chemosensitive [104], (ii) they self-stimulate via Ox receptor 2 [106] and (iii) stimulation inhibits activation of caspase 3 [93] this neuroprotective pathway appears likely. In addition, active caspase 3 in Ox neurons is correlated with the presence of coarse granular Ox immunoreactive staining [77].…”

Section: Mechanisms Of Decreased Ox Immunoreactivitymentioning

confidence: 99%

“…Ox neurons are not apoptotic under hypoxic [109] or excitotoxicity [78] conditions possibly because of the neuronal protective effect of Ox stimulation [108]. Intracerebroventricular OxA given during ischaemia induced by middle cerebral artery occlusion promoted neuronal survival [108]; this action is mediated via Ox receptor activation and the PI3K/Akt pathway [92,93]. Given that (i) Ox neurons are chemosensitive [104], (ii) they self-stimulate via Ox receptor 2 [106] and (iii) stimulation inhibits activation of caspase 3 [93] this neuroprotective pathway appears likely.…”

Section: Mechanisms Of Decreased Ox Immunoreactivitymentioning

confidence: 99%

Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome

et al. 2015

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Infants at risk of sudden infant death syndrome (SIDS) have been shown to have dysfunctional sleep and poor arousal thresholds. In animal studies, both these attributes have been linked to impaired signalling of the neuropeptide orexin. This study examined the immunoreactivity of orexin (OxA and OxB) in the tuberal hypothalamus (n = 27) and the pons (n = 15) of infants (1-10 months) who died from SIDS compared to age-matched non-SIDS infants. The percentage of orexin immunoreactive neurons and the total number of neurons were quantified in the dorsomedial, perifornical and lateral hypothalamus at three levels of the tuberal hypothalamus. In the pons, the area of orexin immunoreactive fibres were quantified in the locus coeruleus (LC), dorsal raphe (DR), laterodorsal tegmental (LDT), medial parabrachial, dorsal tegmental (DTg) and pontine nuclei (Pn) using automated methods. OxA and OxB were co-expressed in all hypothalamic and pontine nuclei examined. In SIDS infants, orexin immunoreactivity was decreased by up to 21 % within each of the three levels of the hypothalamus compared to non-SIDS (p ≤ 0.050). In the pons, a 40-50 % decrease in OxA occurred in the all pontine nuclei, while a similar decrease in OxB immunoreactivity was observed in the LC, LDT, DTg and Pn (p ≤ 0.025). No correlations were found between the decreased orexin immunoreactivity and previously identified risk factors for SIDS, including prone sleeping position and cigarette smoke exposure. This finding of reduced orexin immunoreactivity in SIDS infants may be associated with sleep dysfunction and impaired arousal.

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“…OxA alters intracellular metabolic function and cell survival in neuronal tissue [15, 39, 40, 49]. OxA-induced neuroprotective mechanisms are due in part to increases in HIF-1α and decreased oxidative stress [15, 39, 49].…”

Section: Introductionmentioning

confidence: 99%

“…OxA increases ATP via induction of the transcription factor hypoxia inducible factor-1α (HIF-1α) in mouse hypothalamic tissue under normoxic conditions [39]. In ischemic conditions, OxA promotes the survival of primary cortical neurons in vitro , and suppresses neuronal damage by regulating post-ischemic glucose intolerance in vivo [15, 39, 40, 49]. No published studies have evaluated the potential neuroprotective effects of OxA in the hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

Orexin A decreases lipid peroxidation and apoptosis in a novel hypothalamic cell model

Butterick

Nixon

Billington

et al. 2012

Neuroscience Letters

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Current data support the idea that hypothalamic neuropeptide orexin A (OxA; hypocretin 1) mediates resistance to high fat diet-induced obesity. We previously demonstrated that OxA elevates spontaneous physical activity (SPA), that rodents with high SPA have higher endogenous orexin sensitivity, and that OxA-induced SPA contributes to obesity resistance in rodents. Recent reports show that OxA can confer neuroprotection against ischemic damage, and may decrease lipid peroxidation. This is noteworthy as independent lines of evidence indicate that diets high in saturated fats can decrease SPA, increase hypothalamic apoptosis, and lead to obesity. Together data suggest OxA may protect against obesity both by inducing SPA and by modulation of anti-apoptotic mechanisms. While OxA effects on SPA are well characterized, little is known about the short- and long-term effects of hypothalamic OxA signaling on intracellular neuronal metabolic status, or the physiological relevance of such signaling to SPA. To address this issue, we evaluated the neuroprotective effects of OxA in a novel immortalized primary embryonic rat hypothalamic cell line. We demonstrate for the first time that OxA increases cell viability during hydrogen peroxide challenge, decreases hydrogen peroxide-induced lipid peroxidative stress, and decreases caspase 3/7 induced apoptosis in an in vitro hypothalamic model. Our data support the hypothesis that OxA may promote obesity resistance both by increasing SPA, and by influencing survival of OxA-responsive hypothalamic neurons. Further identification of the individual mediators of the anti-apoptotic and peroxidative effects of OxA on target neurons could lead to therapies designed to maintain elevated SPA and increase obesity resistance.

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Orexins promote survival of rat cortical neurons

Cited by 34 publications

References 30 publications

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

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

Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome

Orexin A decreases lipid peroxidation and apoptosis in a novel hypothalamic cell model

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