Effect of methylene blue on the genomic response to reperfusion injury induced by cardiac arrest and cardiopulmonary resuscitation in porcine brain.
BACKGROUND
Cerebral ischemia/reperfusion injury is a common secondary effect of cardiac arrest which is largely responsible for postresuscitative mortality. Therefore development of therapies which restore and protect the brain function after cardiac arrest is essential. Methylene blue (MB) has been experimentally proven neuroprotective in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. However, no comprehensive analyses have been conducted at gene expression level.


METHODS
Pigs underwent either untreated cardiac arrest (CA) or CA with subsequent cardiopulmonary resuscitation (CPR) accompanied with an infusion of saline or an infusion of saline with MB. Genome-wide transcriptional profiling using the Affymetrix porcine microarray was performed to 1) gain understanding of delayed neuronal death initiation in porcine brain during ischemia and after 30, 60 and 180 min following reperfusion, and 2) identify the mechanisms behind the neuroprotective effect of MB after ischemic injury (at 30, 60 and 180 min).


RESULTS
Our results show that restoration of spontaneous circulation (ROSC) induces major transcriptional changes related to stress response, inflammation, apoptosis and even cytoprotection. In contrast, the untreated ischemic and anoxic insult affected only few genes mainly involved in intra-/extracellular ionic balance. Furthermore, our data show that the neuroprotective role of MB is diverse and fulfilled by regulation of the expression of soluble guanylate cyclase and biological processes accountable for inhibition of apoptosis, modulation of stress response, neurogenesis and neuroprotection.


CONCLUSIONS
Our results support that MB could be a valuable intervention and should be investigated as a therapeutic agent against neural damage associated with I/R injury induced by cardiac arrest.
Martijn
Cécile
C
Department of Surgical Sciences/Anaesthesiology and Intensive Care Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. cecile.martijn@surgsci.uu.se
Wiklund
Lars
L
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism*; D016887:Cardiopulmonary Resuscitation; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D023281:Genomics; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D006323:Heart Arrest / Q000150:complications*; D008297:Male; D008751:Methylene Blue / Q000627:therapeutic use*; D055495:Neurogenesis; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D000071756:Soluble Guanylyl Cyclase; D013552:Swine; D013997:Time Factors
D018696:Neuroprotective Agents; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D008751:Methylene Blue