Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats.
Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood-brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.
Faculty of Life Sciences, University of Manchester, Manchester, UK.
Jesus M
JM
Pradillo
Adam
A
Denes
Andrew D
AD
Greenhalgh
Herve
H
Boutin
Caroline
C
Drake
Barry W
BW
McColl
Eleanor
E
Barton
Spencer D
SD
Proctor
James C
JC
Russell
Nancy J
NJ
Rothwell
Stuart M
SM
Allan
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000187:drug effects; D018696:Neuroprotective Agents; D020556:Neutrophil Infiltration; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015424:Reperfusion; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D016896:Treatment Outcome
D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D018696:Neuroprotective Agents; D011994:Recombinant Proteins