A new taxonomy of neuroprotective agents for stroke appropriate for the reperfusion era

 I've been talking about solving the 5 causes of the neuronal cascade of death in the first week for years! You've finally caught up with stroke-addled me?

A new taxonomy of neuroprotective agents for stroke appropriate for the reperfusion era

Mersedeh Bahr-Hosseini^*Jeffrey L. Saver

• Department of Neurology and Comprehensive Stroke Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States

The advent of the era of highly effective reperfusion(You're NOT HIGHLY EFFECTIVE UNLESS YOU GET TO 100% RECOVERY!) therapy for acute ischemic stroke has reawakened interest in neuroprotective(Wrong terminology, neuroprotection gives no sense of urgency! Call it by its' correct name; the neuronal cascade of death! Sounds important to immediately get fixed, neuroprotection is a milquetoast term saying nothing!) treatments as they are far more likely to be efficacious as synergistic complements to reperfusion rather than standalone interventions. However, testing neuroprotective agents combined with reperfusion mandates not only renewed conduct of trials but also a fundamental reconceptualization of the subclasses of neuroprotection therapies. We propose a new taxonomy of neuroprotective treatment agents appropriate for the reperfusion era that recognizes six broad classes of agents, each targeting a distinct process and time epoch of injury: (1) Bridging neuroprotectives slow infarct expansion in the pre-reperfusion period, (2) Blood–brain barrier stabilizers restore the integrity of BBB before and early after reperfusion, (3) Microcirculation lumen preservers protect arteriolar and capillary endothelial cell integrity deterring the no-reflow phenomenon, (4) Reperfusion injury preventors block inflammatory, oxidative, and other processes that start immediately after reperfusion, (5) Edema reducers avert cerebral swelling and secondary injury due to brain tissue compression and herniation, and (6) Delayed neuroprotectives mitigate injury due to apoptosis and mitochondrial dysfunction in the late post-reperfusion period. This approach also broadly distinguishes neuroprotection from other major treatment strategies, including recanalization, collateral enhancement, and neurorepair. By focusing on broad physiologic targets of action rather than granular molecular mechanisms, this six-fold classification of neuroprotection can inform the design of preclinical studies and human clinical trials, including imaging biomarker endpoint selection and treatment timing. This updated taxonomy may accelerate the translation of cerebroprotective agents from bench to bedside.

Introduction

The elusive dream of neuroprotective treatments for acute ischemic stroke has been rekindled by the advent of highly effective reperfusion therapy. As leading classes of neuroprotective agents are better suited to the treatment of temporary, rather than permanent, ischemia, neuroprotective therapy is more likely to succeed as a synergistic complement to reperfusion treatment than as a standalone intervention. However, an obstacle to further progress is the lingering influence of outmoded frameworks of neuroprotective classes that obscure the best approaches to agent development. The coming of the reperfusion era mandates not only renewed conduct of trials of promising neuroprotective agents but also a fundamental reconceptualization of the subclasses of neuroprotection therapies.

The taxonomies of the past focused almost entirely on only one general physiologic strategy of neuroprotection—slowing the progression of cerebral injury while ischemia is ongoing. In a prototypical example, agents were classified into six categories predominantly according to the molecular mechanisms by which they putatively achieved this single physiologic goal: calcium channel blockers, glutamate antagonists, nitric oxide modulators, gamma-aminobutyric acid potentiators, free radical scavengers, and anti-inflammatory agents (1). This concentration upon molecular subclasses of agents that increase hypoxia tolerance was appropriate at a time when reperfusion was uncommonly achieved and the intra-ischemic period was perforce the predominant target of neuroprotective agent development. But is now out of date. A new taxonomy of neuroprotective treatment agents is needed appropriate for the reperfusion era.

The proposed new taxonomy

We propose an approach that recognizes six broad classes of neuroprotection agents, each targeting a distinct mechanism of injury:

1. Bridging neuroprotectives: These agents slow infarct expansion by blocking the molecular ischemic cascade that elaborates neural injury in ischemic environments. As they act in the intra-ischemic period, they need to be administered soon after (or even prior to) stroke onset and before reperfusion therapies have restored tissue blood flow.

2. Blood–brain barrier stabilizers: These agents restore blood–brain barrier integrity. By stabilizing tight junctions and the neurovascular unit, they reduce the risk of hemorrhagic transformation and restore cerebral autoregulation. If highly effective, blood brain barrier stabilizers could permit thrombolytic drugs to be given at higher than standard doses to increase lysis efficacy.

3. Microcirculation lumen preservers: These treatments avert arteriolar and capillary endothelial cell edema, pericyte contraction, and vasospasm that decrease microcirculatory lumen size, deterring the no-reflow phenomenon (2). They complement lytic and platelet disaggregating treatments that dissolve small thrombi within these vessels and constitute a form of recanalization.

4. Reperfusion injury preventers: These therapies block inflammatory, oxidative, and other processes that cause additional neuronal cell death following achievement of reperfusion. They may be given systemically but also may be given via intra-arterial infusion directly into the reperfused field at the end of an endovascular thrombectomy procedure.

5. Ionic cytotoxic and vasogenic edema reducers: These agents modulate aquaporin and other channels that regulate brain water movement and the size of intracellular and extracellular fluid volumes. They can avert secondary injury due to brain tissue compression and herniation.

6. Delayed neuroprotectives: These therapies block mechanisms of neural injury that are elaborated over several days after the initial ictus, including programmed cell death (apoptosis, necroptosis) and mitochondrial dysfunction. When early reperfusion of tissues averts initial necrotic cell death during the first hours, a substantial proportion of the initially salvaged tissue may experience such delayed injury (3).

Discussion

By focusing on broad physiologic targets of action rather than granular molecular mechanisms, this six-fold classification has direct clinical and development program relevance. Clinical trial designs that recruit a broad population of patients in different stages of ischemic injury will hamper identification of benefit when testing an agent targeted on a specific stage and mechanism of injury. Preferred timing of treatment start varies substantially across the different classes. Bridging neuroprotectives must be given hyperacutely, while ischemia is still ongoing. They therefore require trials with treatment start in the prehospital setting or soon after Emergency Department arrival. Reperfusion injury preventers are optimally started as soon as reperfusion has been achieved (although they can be started earlier so as to already be in place when blood flow is restored). Microcirculatory vessel wall protecters and blood brain barrier stabilizers should be started early, preferably even during the ischemic period but also likely can be helpful if started early after reperfusion. Edema reducers and delayed neuroprotectives can be expected to be still effective if started later, several hours after reperfusion has been established. Figure 1 depicts the proposed six neuroprotective classes, the best treatment start timing relative to reperfusion time, and exemplars of each category.