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https://doi.org/10.1371/journal.pone.0182707
Title: | Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation | Authors: | Modi H.R. Wang Q. Sahithi G.D. Sherman D. Greenwald E. Savonenko A.V. Geocadin R.G. Thakor N.V. |
Keywords: | CD11b antigen glial fibrillary acidic protein inducible nitric oxide synthase interleukin 1beta orexin 1 receptor orexin 2 receptor orexin A tumor necrosis factor biological marker messenger RNA orexin orexin receptor sodium chloride adult animal experiment animal model animal tissue antiinflammatory activity arousal Article behavior assessment coma controlled study electroencephalography heart arrest hippocampus hypothalamus induced hypothermia male nervous system inflammation Neurologic Deficit Scale score neurologic examination neuroprotection nonhuman outcome assessment prefrontal cortex protein localization rat real time polymerase chain reaction return of spontaneous circulation treatment outcome treatment response animal animal behavior brain coma complication drug effects gamma rhythm genetics heart arrest hemodynamics inflammation intranasal drug administration metabolism pathology pathophysiology resuscitation Wistar rat Administration, Intranasal Animals Arousal Behavior, Animal Biomarkers Brain Coma Electroencephalography Gamma Rhythm Heart Arrest Hemodynamics Inflammation Male Orexin Receptors Orexins Rats, Wistar Resuscitation RNA, Messenger Sodium Chloride Treatment Outcome |
Issue Date: | 2017 | Citation: | Modi H.R., Wang Q., Sahithi G.D., Sherman D., Greenwald E., Savonenko A.V., Geocadin R.G., Thakor N.V. (2017). Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation. PLoS ONE 12 (9) : e0182707. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0182707 | Rights: | Attribution 4.0 International | Abstract: | Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1?, iNOS, TNF-?, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic deficit scale score (NDS). Our results indicate that intranasal delivery of ORXA post-CA has an anti-inflammatory effect and accelerates cortical EEG and behavioral recovery. Beneficial outcomes from intranasal ORXA treatment lay the groundwork for therapeutic clinical approach to treating post-CA coma. © 2017 Modi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | Source Title: | PLoS ONE | URI: | https://scholarbank.nus.edu.sg/handle/10635/161174 | ISSN: | 19326203 | DOI: | 10.1371/journal.pone.0182707 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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