Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

Abstract

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.

The Immune System in Stroke: Clinical Challenges and Their Translation to Experimental Research

“…Corpulent rats that are homozygous for the autosomal recessive cp gene (cp/cp) and spontaneously develop obesity, hyperlipidemia, insulin resistance, glomerular sclerosis, and atherosclerosis with enhanced vascular contractility and reduced vascular relaxation have been used for this study (Mangat et al 2007). Peripheral administration of IL-1Ra at the time of reperfusion or with 3h delay to aged lean and Cp rats, reduces ischemic brain injury, BBB breakdown, microglial activation, neutrophil infiltration and expression of MMP-9 and IL-6, which provides further supporting evidence for IL-1Ra as a lead candidate for the treatment of ischemic stroke (Pradillo et al 2012). …”

“…Male, aged rodents often show decreased gray matter injury after experimental stroke compared to young animals, however, an increase in white matter lesions has been demonstrated (Shapira et al 2002;Correa et al 2011). Aging in combination with other risk factors such as obesity or atherosclerosis was found to augment inflammation and BBB injury in the brain (Pradillo et al 2012). Aged animals express altered microglial activation, enhanced expression of proinflammatory cytokines such as IL-6, TNFα and CCL2 (Dinapoli et al 2010), although other studies reported reduced serum IL-6 levels in response to cerebral ischemia (Liu et al 2009).…”

“…Recent data show that brain inflammation is evident in high-fat fed, atherosclerotic ApoE KO mice, and in obese, atherosclerotic corpulent rats even in the absence of any acute cerebrovascular event. These inflammatory changes appear to be IL-1-dependent in mice (Denes et al 2012;Drake et al 2011). Neuroinflammatory changes are also seen in patients at risk of stroke, who present with multiple risk factors for stroke and chronically elevated serum CRP, but no known neurological disease (Drake et al 2011).…”

Streptococcus pneumoniae worsens cerebral ischemia via interleukin 1 and platelet glycoprotein Ibα

“…28,29 Both GPIba blockade and IL-1Ra have been shown to be protective in uninfected animals. 17,18 However, due to the small cerebral injury (that mostly corresponded to the core of the infarct) seen in uninfected animals, we did not expect these interventions to significantly reduce brain injury in control animals in the current experimental model. Importantly, our present results indicate that IL-1-dependent systemic inflammation and pathologies in the central nervous system can develop in response to sustained bacterial infection in vivo, and this disease mechanism is central to the pathologies caused by a clinically important gram-positive bacterium, S. pneumoniae.…”

“…Rats were anesthetized with isoflurane and subjected to cerebral ischemia by transient occlusion of the distal MCA for 60 minutes using a 10-0 suture as described earlier. 17 After experimental stroke, 3 mice and 2 rats were excluded pre hoc due to improper occlusion of the MCA (n 5 2) and surgical artifacts (n 5 3).…”