Please use this identifier to cite or link to this item: 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
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