Pharmacologic Modification of Acute Cerebral Ischemia

The Definition and Role of Cytoprotection

Pharmacologic therapy of ischemic stroke can be split into broad groups on the basis of the sequence and location of physiologic events thought to occur upon occlusion of a cerebral artery, although as in most complex biological systems, these events overlap both temporally and spatially. In some instances, the opportunity for “pretreatment” exists. Ischemic preconditioning, in which a noxious stimulus is given below the threshold of damage, can induce protection when a subsequent deleterious event occurs. The mechanisms of ischemic preconditioning are the focus of ongoing study and important mediators such as Toll-like receptors (TLRs) and astrocyte-mediated mechanisms may play a role. There is mounting evidence that the genomic response to the ischemic cascade can be reprogrammed, thus introducing the concept of prophylactic ischemic stroke therapy in high-risk patients (e.g., those undergoing endovascular or surgical procedures with periprocedural risk of ischemic stroke).

The next group of therapies targets the events occurring within the artery lumen by reversing the arterial occlusion and restoring perfusion to damaged brain tissue. The prototypes of such therapy are thrombolytics, fibrinolytics, and anticoagulants. Reversing arterial occlusion has been the area of greatest clinical success to date in stroke treatment. Other therapies targeting later events will probably have much less impact on outcome than fast removal of the offending arterial occlusion, and it is even possible that further improvement in treatment cannot be achieved unless it is also accompanied by reperfusion of the damaged tissue. Much can be learned from the preclinical and clinical development of these “reperfusion” drugs, and the lessons will be brought into this chapter. However, such therapy is discussed in detail in other chapters and so is not specifically addressed further here.

A third, broad category of pharmacotherapy for stroke targets the consequences of arterial occlusion on the blood vessel wall, neuron, glia, and neuronal environment. Although often labeled neuroprotection, this approach to therapy actually has a wide variety of targets, many of which are non-neuronal, so a more appropriate term would be cytoprotection . Common to this approach is the effort to improve outcome by preventing progression to cellular death of tissue initially damaged by the ischemic event. Although unlikely to salvage irreversibly damaged cells, such therapies may “modify” the biologic perturbations induced at the cellular level in brain tissue whose fate still hangs in the balance. This type of pharmacotherapy is the subject of the present chapter.

A final category of stroke pharmacotherapy aims to augment recovery of brain function by targeting events during the restorative phase occurring after tissue damage is complete. This therapy is the subject of another chapter.

The concept of cytoprotection relies on the principle that delayed cellular injury occurs after ischemia. Neurons suffer irreversible damage after only a few minutes of complete cessation of blood flow. Such a condition might exist during cardiac arrest. In most instances of acute focal brain ischemia, however, if a state of zero blood flow occurs, it would only be in the core of the ischemic region. The larger surrounding penumbral area receives reduced blood flow, which causes loss of normal function that may lead to permanent cellular damage if uncorrected, but allows for recovery if blood flow is restored by either clot lysis or collateral flow.

The presence of good collateral flow has been shown to be associated with improved outcomes and can extend the time window for endovascular therapy (EVT) up to 24 hours in select patients as evidenced by the DAWN (diffusion-weighted imaging [DWI] or computed tomography perfusion Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) and The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE 3) trials. The presence of collateral flow allows delivery of a cytoprotective drug to the threatened tissue. Thus, the existence of collateral flow and penumbra would be important to consider for cytoprotection trials just as it is for delayed reperfusion trials; however, to date, the presence of collateral flow has never been taken into account in clinical trials of cytoprotection.

Because ischemia is clearly a process and not an instantaneous event, there is potential both for modifying the process after the clinical ictus and for altering the final outcome. It is equally apparent from experimental models that if cytoprotective treatments are to succeed, they must be instituted within a few minutes after the onset of ischemia. Previous clinical trials may have failed because such treatment was delayed and was therefore unlikely to render a benefit.

The concept of cytoprotection is not new in the clinical domain. It has been known for years that hypothermia reduces ischemic neuronal injury. Animal models of both global and focal ischemia confirm the beneficial effects of hypothermia. The benefit of hypothermia in treating global cerebral ischemic injury after cardiac arrest has also been demonstrated in humans; ^, however, the optimal depth, method of induction, and ideal patient population for targeted temperature reduction remains uncertain. Despite these uncertainties, preclinical and clinical evaluation of hypothermia provide the first proof that experimental brain cytoprotection, which can be demonstrated so readily in the laboratory, can be translated into human benefit.

Targets of Cytoprotection: The Ischemic Cascade

A major accomplishment of in vivo and in vitro model systems of cerebral ischemia is an understanding of the ischemic cascade . The details of the physiologic events that constitute the brain’s response to injury and this cascade are discussed in detail in other chapters. Each step of this cascade might be a potential target for therapeutic intervention. Several variables exist that may affect the pathobiology of the ischemic cascade and, consequently, the severity of injury; the most important are the depth of blood flow reduction, its duration before reperfusion occurs, its distribution (i.e., global or focal), comorbidities (e.g., diabetes or hypertension), and the adequacy of reperfusion, if one assumes that reperfusion occurs. However, many of the events that have been described seem to follow in a fairly predictable order and are discussed in Chapter 5, Chapter 6, Chapter 7 .

Preclinical Stroke Models

The development of reproducible, relatively simple animal models mimicking cerebral ischemia in humans subsequently led to numerous preclinical studies testing the efficacy of cytoprotective therapies that targeted each of the steps of the ischemic cascade. Although the general nature of the cerebral damage produced by ischemia is the same among species, the severity and other features may differ not only between species but also among various strains and within strains, depending on age, sex, size, and comorbidity. To maintain reproducibility of results of such studies, investigators must pay careful attention to the choice of anesthetic as well as to physiologic variables that must be carefully controlled both during and after ischemia. The standardization of physiologic variables is an important difference between animal stroke models and human stroke, the latter being characterized by great variability in severity and other phenotypic features. Broadly, the models can be divided into those of global forebrain ischemia, which reflect the type of cerebral injury incurred with cardiac arrest, and focal ischemia, similar to what occurs with ischemic stroke in humans. Many permutations of these models exist.

Preclinical Testing of Cytoprotective Therapies

The disturbing reality is that despite the substantial positive effect of cytoprotective drugs in animal stroke models—except for hypothermia after cardiac arrest—results of all clinical trials of this approach to stroke treatment have been neutral (no effect) or negative (harmful). Before we discuss this conundrum, we deal with several general themes that have proved useful in achieving positive results with cytoprotective therapies in preclinical models. Careful attention to these issues will be important in achieving positive results with neuroprotective drugs, either in the laboratory or at the bedside.

Reperfusion Injury

The last 5 years have been transformative for EVT for ischemic stroke, and the infrastructure for how we identify and provide treatment for these patients is evolving. However, despite the proven efficacy of EVT, a substantial percentage of patients with a promising imaging or temporal profile at the time of successful recanalization will still be left with substantial disability. In addition, a small number of patients will develop reperfusion injury that can be associated with worsening cerebral edema and development of hemorrhagic transformation. Proposed mechanisms for reperfusion injury are outlined in Fig. 57.1 . We should expect to see a growing number of patients who do not improve despite successful recanalization as more centers adopt the technology and personnel requirements to offer EVT. This group of patients would be an ideal population for targeted cytoprotection.

Lack of reperfusion despite recanalization of the parent vessel has been termed the “no-reflow phenomenon.” The no-reflow phenomenon has been extensively described in the cardiac literature, but the concept has also been seen in multiple organs, including the brain. ^, Proposed mechanisms of no-reflow in cerebral ischemia include micro-thrombosis or micro-inflammatory mechanisms. ^, Some promising targets include treatments aimed at interleukin (IL)-1, ¹⁹ IL-6, ²⁰ protease-activated receptor-1, and sphingosine-1-phosphate signaling. In addition, microRNA and noncoding RNA as novel treatment targets and biomarkers are emerging in ischemic stroke and are already being evaluated for treatment in other diseases.

Downstream Targets

Many of the initial events in the ischemic cascade, such as release of glutamate and increase in intracellular calcium, occur almost instantaneously, and their effect might not be dampened by a cytoprotective agent even if it is started as early as 1 or 2 hours after the onset of ischemia. Later events in the cascade, such as production of NO and free radicals, inflammatory cytokines, transcription factors, and caspases, may be more effectively targeted by post-ischemic cytoprotective therapies.