Increased cortical expression of the orexin-1 receptor following permanent middle cerebral artery occlusion in the rat

doi:10.1016/S0304-3940(02)00176-3

Neuroscience Letters

Volume 324, Issue 1, 10 May 2002, Pages 53-56

https://doi.org/10.1016/S0304-3940(02)00176-3 Get rights and content

Abstract

The orexins (hypocretins) have recently been implicated in neurodegeneration associated with narcolepsy. Therefore, the current study was designed to investigate changes in the expression of prepro-orexin and the orexin receptors, OX₁R and OX₂R following permanent middle cerebral artery occlusion (MCAO) in the rat. Six and twenty-four hours following MCAO, increased OX₁R mRNA and protein expression (as assessed by Western blotting and immunohistochemistry) was detected in the ischaemic cortex compared with control tissue. In contrast, however, no increase in OX₂R mRNA was detected at any time-point and prepro-orexin levels in the cortex were below assay detection levels. This study shows that orexin receptor localization is altered following cerebral ischaemia. The development of selective orexin receptor antagonists will be crucial in establishing a role for this family of novel peptides in the mechanisms underlying ischaemic cell death.

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Cited by (35)

Role of orexin-A in experimental autoimmune encephalomyelitis
2016, Journal of Neuroimmunology
Citation Excerpt :
OX-A also can alleviate cognitive deficits produced by sleep deprivation (Deadwyler et al., 2007) and inactivation of OX1R impairs spatial learning and memory (Akbari et al., 2006). Loss of orexinergic neurons or dysfunction in the orexinergic system have been observed in several acute and chronic CNS diseases such as Alzheimer (Fronczek et al., 2012), narcolepsy (Arango et al., 2014), an animal model for Parkinson's disease (Long-Biao et al., 2010) and stroke (Irving et al., 2002). The reported findings about orexinergic system and MS are controversial.
The aim of this study was to evaluate the effects of orexin-A (OX-A) on behavioral and pathological parameters and on gene expression of some multiple sclerosis-related peptides in a model of experimental autoimmune encephalomyelitis (EAE). EAE was induced by subcutaneous administration of MOG 35–55. Following immunization, the treatment was initiated by using SB.334867 (orexin-1 receptor antagonist) and/or OX-A. Locomotor activity and exploratory behaviors were monitored using open field and T-maze continuous alternation task (T-CAT) respectively. Pain sensitivity was assessed by hot-plate test. Histopathological assessments were performed by H&E staining. The expression of TGF-β, MBP, MMP-9, IL-12, iNOS and MCP-1 were measured using real-time PCR method in lumbar spinal cord. OX-A administration in EAE mice remarkably attenuated the clinical symptoms, increased latency response in hot plate test, inhibited infiltration of inflammatory cells, up-regulated mRNA expression of TGF-β as well as MBP and down-regulated mRNA expression of iNOS, MMP-9 and IL-12. In contrast SB.334867 administration in EAE mice deteriorated the clinical symptoms, decreased the alternation in T-CAT, increased infiltration of inflammatory cells, down-regulated mRNA expression of TGF-β and MBP and up-regulated mRNA expression of iNOS. Results of this study suggest that the orexinergic system might be involved in pathological development of EAE. These findings suggest orexinergic system as a potential target for treatment of multiple sclerosis.
Effects of changes in energy homeostasis and exposure of noxious insults on the expression of orexin (hypocretin) and its receptors in the brain
2013, Brain Research
Citation Excerpt :
Four of the 5 studies of ischemia, showed increased OxR1 expression (Table 3). Yet, it is important to note that this change was specific to hippocampal and cortical regions, not the hypothalamus, in keeping with the sensitivity of these regions to hypoxic damage (given their greater blood supply) (Irving et al., 2002). One study used middle cerebral occlusion to induce ischemia and reported a decrease in OxA expression in the hypothalamus (Kitamura et al., 2010).
This review summarizes data regarding the brain expression of the orexin (hypocretin) system including: prepro-orexin (PPO), orexin A (OxA), orexin B (OxB) and the two orexin receptors 1 and 2 (OxR1, OxR2). Clinical data is limited to OxA and OxB in cerebral spinal fluid and serum/plasma, thus necessitating the development of animal models to undertake mechanistic studies. We focus on changes in animal models that were either exposed to a regime of altered sleep, metabolic energy homeostasis, exposed to drugs and noxious insults. Many more expressional studies are available for PPO, OxA and OxB levels, compared to studies of the receptors. Interestingly, the direction and pattern of change for PPO, OxA and OxB is inconsistent amongst studies, whereas for the receptors, there tends to be increased expression for both OxR1 and OxR2 after alterations in energy homeostasis, and an increased expression after noxious insults or exposure to some drugs. The clinical implications of these results from animal models are discussed in light of the findings from human studies, and future research directions are suggested to fill knowledge gaps with regard to the orexin system, particularly during early brain development.
Orexin A decreases lipid peroxidation and apoptosis in a novel hypothalamic cell model
2012, Neuroscience Letters
Citation Excerpt :
While OxA signaling promotes SPA [21,22,44], and increased SPA protects against obesity [43,44], whether OxA protects against HFD-induced oxidative stress in the hypothalamus is unknown. Multiple models link changes in OxA or orexin receptors to neurodegenerative conditions [13,17], suggesting that orexin signaling pathways help maintain neuronal survival. Increased survival of neurons responsible for mediating SPA might explain the long-term benefits of OxA in obesity resistance, but how OXA-induced intracellular mechanisms affect short-term neuronal survival or SPA response is poorly understood.
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.
Ischemic stroke and glucose intolerance: A review of the evidence and exploration of novel therapeutic targets
2012, Journal of Pharmacological Sciences
Stroke is one of the leading causes of death and disability worldwide. It is well known that hyperglycemia and/or diabetes potentially exacerbate the neuronal damage observed following ischemic stroke. Recent reports have shown that hyperglycemia/glucose intolerance may be induced by cerebral ischemic stress, and that normalization of blood glucose levels during the first 48 h of hospitalization appears to confer greater survival outcomes in stroke patients. However, the mechanisms underlying post-ischemic glucose intolerance remain unclear. Here, we review research to date on the mechanisms through which ischemic neuronal damage develops and on the role of post-ischemic glucose intolerance focusing on insulin and adiponectin signaling and communication between the brain and peripheral tissues. The relationship between ischemic neuronal damage and post-ischemic glucose intolerance is also discussed. With respect to therapeutic options, in addition to traditional post-stroke therapies, we also discuss the effect of anti-diabetic drugs and glucose-sensing neuropeptides on the development of the post-ischemic glucose intolerance and neuronal damage. In conclusion, we support the idea for focusing research on the development of post-ischemic glucose intolerance as a new therapeutic target for the stroke patients.
Effect of orexin-A on post-ischemic glucose intolerance and neuronal damage
2011, Journal of Pharmacological Sciences
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
This article has been retracted at the request of the Authors because an Investigation Committee established by Kobe Gakuin University has found that in the Figures 4A and 4B, multiple numbers of the original raw data were changed. Hence, the Figures were different from real Figures obtained from original raw data and the significant difference in the Figures 4A and 4B was not obtained.
The effect of orexin-A on the pathological mechanism in the rat focal cerebral ischemia
2010, Neuroscience Research
Orexin-A is a neuropeptide involved in the control feeding, arousal or sleep behavior in the hypothalamus. In the present study, the cortex and lateral hypothalamus of rats subjected to middle cerebral artery occlusion (MCAO)-reperfusion brain injury were examined by double immunofluorescence staining. The number of orexin-A-expressing neurons in the non-ischemic side was significantly lower than the ischemic side. Next, orexin-A was administered intracerebroventricularly followed by the induction of MCAO-reperfusion injury. Administration of orexin-A at 0.3 nmol significantly reduced the brain infarct area. The results suggested that orexin-A alters the pathological mechanisms involved in brain ischemia and has a neuroprotective effect.

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Increased cortical expression of the orexin-1 receptor following permanent middle cerebral artery occlusion in the rat

Abstract

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Cell

Neurosci. Lett.

Neuroscience

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Mol. Brain Res.

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Lancet

Cell