pii: sp-00538-15

http://dx.doi.org/10.5665/sleep.5138

EDITORIAL

More Wake, Less Stroke Commentary on Pace et al. Identification of sleep-modulated pathways involved in neuroprotection from stroke. SLEEP 2015;38:1707–1718. Matteo Cerri, MD, PhD Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy

Stroke is among the most common and devastating cardiovascular diseases in the western world,1 but at the moment, the only effective treatment for this condition is reperfusion therapy, which can only be delivered in a minority of cases.2 Because of the long-term consequences of stroke, and considering that in the USA, it is the primary cause of disability, the cost of this condition is a major contributor to health expenses, and it has a substantial social cost for families of patients affected by stroke.3 For these reasons, research into new therapeutic targets to improve the clinical outcome is urgently needed. In this issue of SLEEP, Pace and colleagues offer a very clever and integrated approach to begin the search for new therapeutic targets for stroke, focusing especially on reducing the neural damage caused by ischemia.4 Their report originates from one of the findings from the same research group, in which they observed that sleep deprivation is detrimental for stroke outcome when sleep loss occurs after the stroke, while it appears to be beneficial when it takes place before the stroke.5 Such an apparently counterintuitive finding can be explained in the light of a peculiar biological effect called preconditioning.6 According to the definition, preconditioning derives from the application of a potential harmful stimulus, that is near to but below the threshold of cell damage, and which promotes the tolerance of the cell to subsequent ischemic injury.6 It is interesting to note that, within this theoretical frame, sleep deprivation is the potentially harmful stimulus, activating some cellular pathway thought to provide prophylaxis to the subsequent ischemic damage. Therefore Pace4 designed an experiment to search for such a pathway. The report of Pace shows how gene expression is changed by an experimental procedure that reproduces stroke in rodents, and how such a change is modified by 6 hours of sleep deprivation before the stroke. Their precise and complete experimental plan was clearly designed with the statistical analysis in mind that would later be required to interpret the findings, and not vice versa. The use of the Ingenuity Pathway Analysis, in addition, permits the extraction of effective knowledge from an omics experiment that would otherwise contain too many data to lead anywhere. It is a pleasure to see such a highly integrated approach, where physiology, neurology, molecular

biology, and bioinformatics complement each other to reach a scientific result. The results of study by Pace indicate that the molecular response to stroke was characterized by the upregulation of many genes involved in the modulation of the immune response and/ or in the control of the cell cycle. All these responses were attenuated by sleep deprivation, confirming the idea that the preconditioning may be effective by blunting the immune response to the ischemic insult. It was even more interesting to discover that a set of upregulated genes may also have provided neuroprotection, and notably, among them, PMch and Hcrt, the genes for, respectively, the neuropeptides melanin concentrating hormone (MCH) and hypocretin/orexin (Hcrt). While hypocretin/orexin had already been shown to be involved in neuroprotection,7,8 the same role for PMch had not been suggested before and could open new scenarios for drug discovery. It is quite interesting that both hypocretin/orexin and MCH may be involved in neuroprotection, since both peptides share many characteristics: both are synthesized in neurons located within the lateral hypothalamus in reciprocally segregated sets of neurons; both types of neurons have widespread projections across the central nervous system; both neurons are synaptically connected to each other; and both are involved in the regulation of a behavioral state (wakefulness for Hcrt and REM sleep for MCH).9 In consideration of the high divergence that Hcrt and MCH neurons have, it is intriguing to think that the release of one or the other neuropeptides or maybe both, can trigger the activation of the preconditioning pathway in many target neurons. This finding is, of course, just the beginning, and more detailed work on how Hcrt and MCH induce preconditioning will be required. In the meantime, what Pace and colleagues4 have shown is a valid new target to explore in order to reduce the damage and the cost of stroke.

DISCLOSURE STATEMENT Dr. Cerri has indicated no financial conflicts of interest. REFERENCES

1. Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke 1996;27:1459–66. 2. Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-toneedle times within 60 minutes. Circulation 2011;123:750–8. 3. Wang G, Zhang Z, Ayala C, Dunet DO, Fang J, George MG. Costs of hospitalization for stroke patients aged 18-64 years in the United States. J Stroke Cerebrovasc Dis 2014;23:861–8.

Submitted for publication September 2015 Accepted for publication September 2015 Address correspondence to: Matteo Cerri, MD, PhD, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Piazza di Porta S. Donato, 2, Bologna, 4126 Italy; Tel: 00390512091731; Email: [email protected] SLEEP, Vol. 38, No. 11, 2015

CITATION Cerri M. More wake, less stroke. SLEEP 2015;38(11):1671–1672.

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Editorial—Cerri

4. Pace M, Baracchi F, Gao B, Bassetti C. Identification of sleepmodulated pathways involved in neuroprotection from stroke. Sleep 2015;38:1707–18. 5. Cam E, Gao B, Imbach L, Hodor A, Bassetti CL. Sleep deprivation before stroke is neuroprotective: a pre-ischemic conditioning related to sleep rebound. Exp Neurol 2013;247:673–9. 6. Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol 2009;8:398–412.

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7. Kitamura E, Hamada J, Kanazawa N, et al. The effect of orexin-A on the pathological mechanism in the rat focal cerebral ischemia. Neurosci Res 2010;68:154–7. 8. Kotan D, Deniz O, Aygul R, Yildirim A. Acute cerebral ischaemia: relationship between serum and cerebrospinal fluid orexin-A concentration and infarct volume. J Int Med Res 2013;41:404–9. 9. Konadhode RR, Pelluru D, Shiromani PJ. Neurons containing orexin or melanin concentrating hormone reciprocally regulate wake and sleep. Front Syst Neurosci 2015;8:244.

Editorial—Cerri

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