Interleukin-1 in Stroke

Abstract

IL-1Ra is a promising treatment for both ischemic and hemorrhagic stroke. There are extensive preclinical data in diverse models of cerebral ischemia, including aged and comorbid animals, and a recent cross-laboratory validation study. IL-1Ra is safe and well tolerated in patients with ischemic or hemorrhagic stroke and reduces inflammatory markers associated with worse outcome. However, on a cautionary note, it should be noted that many promising treatments for stroke have been in a similar position to IL-1Ra over the years and have failed to successfully translate to the clinic. Reasons for these failures and the predictive ability of stroke models have been discussed in many articles, as have suggested improvements for future research that might improve translation.65-68 In respect of these previous experiences, it is important therefore to highlight gaps in current knowledge relating to inhibition of IL-1 in stroke. There remains limited data on the therapeutic window for IL-1 inhibition, although one recent study reports efficacy of IL-1Ra up to 12 hours after intravenous treatment in rat MCAO.69 IL-1 exerts several biological effects that could improve functional recovery, including the release of growth factors, cell proliferation, and angiogenesis. Therefore, it is important to determine whether there is a limited window of opportunity to inhibit IL-1 poststroke and that if this is exceeded detrimental consequences might ensue. To our knowledge there are no studies investigating this, for example, by blocking IL-1 at extended time points after stroke onset. There are also no studies testing protective effects of IL-1 inhibition in larger species and limited data on long-term functional outcomes. Also, there is a need for more studies using thromboembolic models of stroke where reperfusion is obtained via tissue-type plasminogen activator to mimic the clinical situation. Finally, IL-1Ra is a large protein with restricted brain penetration and relatively rapid elimination from the body. Although such features may actually be advantageous if acute inhibition of IL-1 in the periphery is what is optimal in treating stroke, there is a need for research on alternative approaches to block IL-1 such as caspase-1 inhibitors, antibodies, and small molecules. Finally, there are no studies investigating the effects of IL-1Ra in combination with other agents, either novel putative stroke treatments or existing medications that many patients with stroke will be taking, such as antiplatelets, antihypertensives, and statins. As to the future, a phase 2 study investigating the effects of IL-1Ra on perihematomal edema in ICH is funded and will commence in 2018, after initial studies investigating the time course of IL-1 within the hematoma of patients participating in the MISTIE (Minimally Invasive Surgery Plus rT-PA for ICH Evacuation) III trial (ISRCTN 81927110; UKCRN ID:20062) and the extent and colocalization of blood-brain barrier permeability and perihematomal microglial activation in patients with acute ICH (UKCRN ID:19650). In addition, a phase 3 multicenter efficacy trial is planned in SAH. Further considerations before phase 3 testing in ischemic stroke include intra-arterial versus peripheral route of administration in patients receiving thrombectomy, patient selection, sample size considerations, and choice of outcomes. Finally, in view of its development in ischemic and hemorrhagic stroke, IL-1Ra could also be a candidate treatment for the prehospital paramedic setting, before brain imaging.