Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

Abstract

While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased. R/I can increase lesion size and also worsen blood barrier breakdown and lead to brain edema and hemorrhage. A major mechanism underlying R/I is that of poststroke inflammation. The poststroke immune response consists of the aberrant activation of glial cell, infiltration of peripheral leukocytes, and the release of damage-associated molecular pattern (DAMP) molecules elaborated by ischemic cells of the brain. Inflammatory mediators involved in this response include cytokines, chemokines, adhesion molecules, and several immune molecule effectors such as matrix metalloproteinases-9, inducible nitric oxide synthase, nitric oxide, and reactive oxygen species. Several experimental studies over the years have characterized these molecules and have shown that their inhibition improves neurological outcome. Yet, numerous clinical studies failed to demonstrate any positive outcomes in stroke patients. However, many of these clinical trials were carried out before the routine use of revascularization therapies. In this review, we cover mechanisms of inflammation involved in R/I, therapeutic targets, and relevant experimental and clinical studies, which might stimulate renewed interest in designing clinical trials to specifically target R/I. We propose that by targeting anti-inflammatory targets in R/I as a combined therapy, it may be possible to further improve outcomes from pharmacological thrombolysis or mechanical thrombectomy.

Keywords: endovascular treatment; hyperglycemia; ischemic stroke; microglia; postischemic inflammation; reperfusion injury; revascularization; tissue plasminogen activator.

Figure 1

Ischemia-induced inflammation in association with reperfusion injury. Once brain ischemia occurs, oxygen and glucose supplies are reduced. If ischemia occurs for more than a certain time period (likely a few hours, but the precise duration is not well established) and blood flow is restored (reperfusion), worsened injury can paradoxically occur to the brain. This is often referred to as reperfusion injury. A major component of reperfusion injury involves subsequent inflammatory reactions induced through various mechanisms. Reperfusion leads to the introduction of ROS from oxygenated blood and can stimulate an immune response in the ischemic brain. Necrotic, ischemia-injured cells lyse and release their contents into the extracelluar space which can act as ligands for various immune receptors. Among these include nucleic acids which are one of many described damage-associated molecular pattern (DAMPs, see text for details). DAMPs can then bind TLRs and stimulate several inflammatory responses (microglial activation, overexpression of proinflammatory cytokines, chemokines) which lead to worsened brain injury. Inflammatory signaling also causes immune cells to generate more effector molecules such as ROS and iNOS/NO. In the periphery, cytokines and adhesion molecules can attract circulating immune cells to the ischemic brain where they infiltrate the damaged tissue and further amplify ischemic injury. Some circulating immune cells and platelets can also plug the microvasculature of the ischemic brain and cause secondary reductions in local CBF. In addition to brain cells, these inflammatory reactions can also cause damage to brain endothelia causing BBB disruption, edema and hemorrhagic transformation. Thus, the restoration of CBF can cause more extensive brain tissue damage. This vicious cycle is often called reperfusion injury. ROS, reactive oxygen species; DAMPs, damage-associated molecular patterns; TLR, toll-like receptor; MMPs, matrix metalloproteinases; iNOS, inducible nitric oxide synthase; NO, nitric oxide; BBB, blood–brain barrier; CBF, cerebral blood flow.