Interleukin-1 Receptor Antagonists as a Stroke Treatment
Researchers here investigate a class of drug that blocks interleukin-1 receptor activity, something that has been found to reduce cell death and improve regeneration following stroke. This form of interference in cellular metabolism lowers the level of inflammation, but that may or may not be the most important mechanism in the outcome for stroke patients; it is plausible, but the details remain to be determined conclusively at this point.
The pro-inflammatory cytokine interleukin-1 (IL-1) is a major driver of inflammation, with well documented detrimental effects in multiple preclinical models of systemic inflammatory disease as well as in cerebral ischemia. To this end, the selective, naturally occurring competitive inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1Ra) has shown potential as a new treatment for stroke. More specifically, in a number of experimental stroke paradigms IL-1Ra reduces infarct volume and improves long term functional outcome, including in co-morbid animals. However, exact mechanisms by which IL-1Ra is neuroprotective are yet to be fully established.
While much research has focused on limiting ischemic damage in the initial stages of acute reperfusion, it is also important to understand mechanisms that underpin brain repair following injury and develop strategies that enhance reparative endogenous processes, including adult neurogenesis. Ischemic injury elicits a robust neurogenic response by stimulating production of neuronal progenitor cells (NPCs) in distinct neurogenic regions, which include the subventricular zone (SVZ) and the subgranular zone (SGZ), to generate new functional neurons. Though mechanisms underlying post-stroke neurogenesis and the influence of inflammation on these processes are still poorly understood, it has been observed in young and aged animals that inflammation impairs both basal levels of neurogenesis and attenuates the neurogenic response triggered by central nervous system (CNS) injury via induction of the pro-inflammatory cytokines. IL-1, for example, reduces the proliferation and differentiation of NPCs to neurons in pathologies such as stress and depression, effects reversed by administration of IL-1Ra.
Here, we explored how inhibition of IL-1 actions by clinically relevant, delayed administration of subcutaneous IL-1Ra affects stroke outcome and neurogenesis up to 28 days after experimental ischemia, in aged/co-morbid and young rats. All experiments were performed using 13-month-old male, lean and corpulent (Cp) rats and 2-month-old Wistar rats. Cp rats are homozygous for the autosomal recessive cp gene (cp/cp), and spontaneously develop obesity, hyperlipidemia, insulin resistance, glomerular sclerosis, and atherosclerosis. Delayed IL-1Ra administration at 3 and 6 hours reperfusion in aged lean, aged Cp and young Wistar rats induced a significant reduction in infarct volume at 24 hours and 7 days of reperfusion, and a significant reduction in cortex loss at 28d in young Wistar rats. Reductions in infarct volume at 24 hours of reperfusion were 37%, 42% and 40% in aged lean, aged Cp and young Wistar rats respectively. IgG staining at 7 days reperfusion revealed a reduction of 40%, 48% and 46% in blood-brain barrier (BBB) damage in IL-1Ra treated aged lean, aged Cp and young Wistar animals respectively, versus their placebo-treated counterparts. A reduction of 26% was also observed at 14d reperfusion in young Wistar rats treated with IL-1Ra versus their placebo counterparts.
Our findings demonstrate that subcutaneous administration of IL-1Ra is neuroprotective in young and aged animals with multiple risk factors for stroke and increases post-stroke neurogenesis. It has previously been observed that delayed administration of IL-1Ra exerts neuroprotective effects at acute time points following experimental ischemia. Here we extend these findings to show that the early beneficial effects of IL-1Ra persist for at least 7 days in aged/co-morbid animals and for 28 days in young/healthy animals. Our data show that although 13-month-old corpulent rats had a plethora of stroke associated co-morbidities, infarct volumes were of a similar size to aged leans, suggesting that the extent of ischemic damage was close to maximal and that no further increase was possible. Conversely, younger rats were more resistant. This suggests that age is the primary variable that increases the brain susceptibility to infarction following an ischemic stroke. However, despite reaching maximal levels of infarction, tissue is still salvageable under these circumstances if IL-1Ra is administered within a therapeutic window.
Furthermore, our results indicate that although the delayed administration of IL-1Ra (3 and 6 hours from reperfusion onset) reduces infarct volume, it produces an increase on cellular proliferation and migration of immature neurons versus placebo counterparts in the SVZ following stroke in young and aged/co-morbid rats, suggesting that a reduced inflammation of the tissue fosters a more efficient repair of the damaged tissue. We also show that IL-1Ra increases the number of new integrated neurons in areas surrounding the infarct lesion in young animals compared to placebo groups a result that correlates with improvements in motor and behavioral sub-acute outcomes. The benefits of IL-1Ra are therefore not limited to inducing neuroprotection, but also favor and promote neurorepair mechanisms. We conclude that further studies are required to fully elucidate the mechanisms through which IL-1Ra may be mediating its beneficial, neurogenic effects.