Therapeutic targets for neuroprotection in acute ischemic stroke: lost in translation?

Abstract

The development of a suitable neuroprotective agent to treat ischemic stroke has failed when transitioned to the clinical setting. An understanding of the molecular mechanisms involved in neuronal injury during ischemic stroke is important, but must be placed in the clinical context. Current therapeutic targets have focused on the preservation of the ischemic penumbra in the hope of improving clinical outcomes. Unfortunately, most patients in the ultra-early time windows harbor penumbra but have tremendous variability in the size of the core infarct, the ultimate predictor of prognosis. Understanding this variability may allow for proper patient selection that may better correlate to bench models. Reperfusion therapies are rapidly evolving and have been shown to improve clinical outcomes. The use of neuroprotective agents to prolong time windows prior to reperfusion or to prevent reperfusion injury may present future therapeutic targets for the treatment of ischemic stroke. We review the molecular pathways and the clinical context from which future targets may be identified.

FIG. 1.

Approximate timeline of molecular pathway onsets following ischemic stroke. Obstruction of blood flow to the brain via the presence of a thrombosis, embolism, or systemic hypoperfusion results in ischemic stroke. The subsequent lack of oxygen and glucose results in the initiation of the depicted ischemic cascade that ultimately results in neuronal death. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

Example of clinical progression of ischemic stroke in the setting of a large artery occlusion. A 50-year-old patient presents at 15 h from symptom onset with a left-sided weakness and was found to have (A) occlusion of the right internal carotid artery (black arrow) on CT angiography. A CT perfusion was performed to estimate penumbra and showed (B) reduction of the cerebral blood flow to the right middle cerebral artery territory, and (C) prolongation of the mean transit time to the right hemisphere. MRI of the brain was performed to determine the core infarct size; in (D) and (E) the diffusion weighted sequence reveals a small core (white arrows) relative to the perfusion defect noted on CT perfusion imaging. The patient was admitted to the neuro intensive care unit and his blood pressure was raised with vasopressor agents to attempt to maintain perfusion to the right hemisphere. At 24 h from symptom onset, his weakness worsened and a repeat MRI of the brain revealed (F) and (G) extension of the infarct on diffusion weighted sequences (white arrows). (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 3.

Example of reperfusion therapy beyond traditional time window. A 75-year-old patient presented with left sided weakness 3 days earlier and was noted to have (A) and (B) a small diffusion weighted core (white arrows) infarct on MRI. (C) CT perfusion imaging showed prolongation of the mean transit time to the right hemisphere and provided an estimate of penumbra. (D) A cerebral angiogram revealed the presence of a right middle cerebral artery occlusion (black arrow) that was the culprit for the mismatch. (E) A stent was successfully implanted (dashed black arrow) and revealed marked improvement in the (F) mean transit time to the right hemisphere. The patient had marked improvement in his weakness and returned to near baseline function at 30 day follow up. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

Approximate timeline of molecular pathway onsets following reperfusion. The restoration of blood flow to the brain after ischemic stroke allows the reestablishment of glucose and oxygen supply to the damaged area. Despite the benefits of restoring blood flow to the brain, reperfusion injury has become an intensive area of study, as this process results in the activation of many molecular pathways that enhance neuronal death. The approximate timing of these events is shown above. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 5.

Clinical example of reperfusion injury in the setting of reperfusion therapy. A 65-year-old woman presented with recurring episodes of right sided weakness and speech difficulties. (A) A CT perfusion image showed a large area of reduced perfusion to the left hemisphere (white arrow). (B) Cerebral angiography was performed and showed a severe stenosis of the left internal carotid artery (black arrow). (C) A carotid stent (dashed black arrow) was placed to revascularize the severe narrowing but was complicated with (D) an embolus to the left middle cerebral artery (black arrow). (E) A stent was implanted in the left middle cerebral artery (dashed black arrow) with successful reperfusion achieved at 60 min from the initial time of the embolus. (F) A large hemorrhage (dashed white arrow) was noted within a sizeable infarct despite rapid reperfusion of the iatrogenic embolus. The mechanism was likely reperfusion injury. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).