Introduction

Since the inception of Translational Stroke Research, numerous significant scientific breakthroughs have been published as peer-reviewed contributions, and some have lead the way for significant advances in the stroke field, opening up new ways to think about stroke therapy research and development [1–5], animal models [6–9], mechanisms of injury and the ischemic cascade [3, 10–14], and clinical trials [1, 15–18]. Many of the scientific advances are being directly applied to discover therapeutic approaches, but there remain some gaps in the systematic approaches being used to treat stroke patients. The best use or way of using neuroprotective agents and the clinical trial to adequately test them is somewhat of an unfinished puzzle. We have yet to put the pieces together to assemble a coherent picture and have success with a neuroprotectant.

“Learning is not attained by chance, it must be sought for with ardor and attended to with diligence.”―Abigail Adams (1744–1818).

Translational Stroke Research: Ways and Means

The development of crucial therapies for acute ischemic stroke (AIS) has come to a standstill in many settings including the academia and industry, not because of lack of innovation, novel drugs, or efficacy in standardized accepted animal models, but for two other primary causes. First, for academics, research has slowed or even stopped in some laboratories due to the lack of government and private funding support for translational stroke research. Second, in the pharmaceutical and biotechnology industry, development of novel drugs is not being pursued due to the failure of many high-impact clinical trials (e.g., SAINT, DIAS, NEST) and their cosmic repercussions. For example, the development of novel drug approaches [19–22], thrombolytics [23–26], and devices [27–29] has slowed or halted due to late-stage clinical trial futility even with some efficacy in early rounds of clinical trials. With the exception of tissue plasminogen activator (rt-PA) [30] and tenecteplase [31, 32, but also see 33], which has a higher fibrin binding specificity than rt-PA and possibly greater resistance to inactivation by plasminogen activator inhibitor-1 (PAI-1, serpin-1), an endogenous inhibitor of plasminogen activator compared to rt-PA, there continues to be a lack of significant efficacy of all forms of treatment in a diverse and heterogeneous patient population. It should be noted that both thrombolytics were equally efficacious in preclinical studies [34].

There is the perception amongst some in the community that current animal models may be inadequate for stroke therapy development. This article hypothesizes that the animal models used for the development of neuroprotective agents are more than adequate [35, 36], and one model has even been described as the gold standard [7–9] for drug development. It appears that the failure of many clinical trials described in the seminal review by O’Collins et al. [37] and in many recent reviews [7, 38, 39] may not only be related to poor drug selection criteria [40, 41], but also to clinical trial design, in particular, time to treatment exceeding that which could be extrapolated from translational research studies. Since a revolutionary way to treat stroke is immediately necessary, the utilization of established advanced clinical networks such as field administration of stroke therapy—magnesium (FAST-MAG), and novel screening methods such as that used by the Regensburg stroke mobile project (RSMP) transcranial sonography units is required to help diagnose stroke in the field in order to provide the patient with the best possible opportunity for neuroprotective treatment and subsequent recovery.

The FAST-MAG Network

The establishment of the impressive FAST-MAG network by Saver and colleagues [42–44] beginning in 2003, supported by the National Institutes of Health (NIH), is a major accomplishment in the field of stroke victim care. The purpose of FAST-MAG, a multicenter, randomized, double-blind trial, is to demonstrate that paramedic initiation of the neuroprotective agent magnesium sulfate in the field is an effective and safe treatment for acute stroke. The network has allowed the Los Angeles clinical community to address some of the basic therapeutic window treatment concerns related to neuroprotection in stroke. Because of the rapid pace of developments in FAST-MAG, theoretically, it is now possible to effectively treat patients in the field (i.e., emergency medical services (EMS) vehicles) within the “golden hour,” the time frame where brain tissue can still be salvaged (see below) [45] to minimize stroke damage. This could not have been accomplished without the validated Los Angeles Prehospital Stroke Screen (LAPSS) [22], mobile informed consent documentation [46, 47] and other evolving methods to diagnose stroke in the field (see below).

The RSMP Network

The Regensburg project is an advanced network of mobile paramedics and stroke neurologists with the background necessary to perform and accurately read transcranial color-coded sonography (TCCS) in the field [48]. The major advantage of this network is the ability of paramedics and clinicians to perform the studies en route to the hospital. In the preliminary study conducted in 2008, there was an 80 % efficiency rate of vessel visualization, which could be accomplished within 2 min [49]. In the follow-up trial conducted in 2010–2011, 113 patients were enrolled, and the effectiveness of field diagnosis was at the 90 % level for positive prediction of a middle cerebral artery (MCA) occlusion and 98 % for negative prediction. The authors indicated that TCCS examination was completed within 5.6 min of reaching the stroke victim in the field, and subsequent transport to the hospital for care was accomplished within 53 min. More recently, Holscher et al. [50] have delved further into the mobile brain rescue units that are available not only in Germany, but the state of the art will soon be available in San Diego, CA. In Germany, prehospital ultrasound can be done in both ambulances and helicopters almost guaranteeing rapid treatment to stroke victims. One hour is a modest time frame to begin to treat patients with either a thrombolytic or a neuroprotective agent to prevent or reverse ischemia-induced neurodegeneration [51].

Thrombolytic Therapy

The thrombolytic rt-PA that was first approved by the FDA in 1996 is now widely accepted as a standard of care, but it is underutilized in most communities. Alteplase has been shown to be effective up to 4.5 h after a stroke [52, 53], but it is currently FDA-approved for use within a 3-h therapeutic window. It is estimated that less than 7 % of stroke patients are being treated with rt-PA in the USA [54–56] despite the fact that rt-PA is quite useful in up to 50 % of patients provided with rt-PA as a treatment option, depending on the type of ischemic stroke [30]. Cost analysis based upon the utilization of rt-PA [57], within 3–4.5 h after stroke onset, clearly shows incremental benefit in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0–19, compared to no treatment. This translated into substantial benefit in terms of quality-adjusted life-years (QALY) for the stroke victim. The correlative analysis showed reduced benefit in patients with an NIHSS score >19 and also pointed to no significant benefit in diabetic patients or patients with atrial fibrillation [57]. We still have to deal with many important shortcomings of the drug including the fact that rt-PA does not confer neuroprotection, and there is a significant risk of hemorrhagic transformation (HT) or intracerebral hemorrhage (ICH) in approximately 3 to 6 % of patients treated within 3–4.5 h of a stroke [58]. Moreover, the odds ratio for mortality rate increases substantially after 4 h [58].

Of importance to the topic of this editorial is the measure known as door-to-needle (DTN) time. The recommended DTN time for thrombolytic therapy administration is less than 60 min [59–62]. However, historically, rt-PA has been administered well in excess of that recommendation (Cochrane review [63]). For example, in the original NINDS rt-PA clinical trial [30], the administration time was stratified between 0 and 90 min and 91–180 min. Subsequent clinical trials have attempted to expand the therapeutic window for rt-PA [52, 64], rather than reduce the time to treatment. Eighteen years after the FDA approval of rt-PA, the treatment is still underutilized [54, 56], but there has been considerable improvement in DTN [65, 66]. Recently, Saver et al. [67] completed extensive data analysis on data collected from 58,353 patients receiving rt-PA within 4.5 h of symptom onset. In keeping with “time is brain” (see below), the analysis of onset to treatment time (OTT) showed a direct correlation with measures important to the patient, including reduced mortality, reduced hemorrhage, increases functional independence, and increase time of discharge. Thus, the establishment of rapid treatment networks should now be used to our advantage, and the patient’s advantage, to provide stroke victims with neuroprotective drugs which have been developed using RIGOR guidelines [1, 68, 69], according to STAIR criteria [70, 71], and deemed safe using standard preclinical assessment [72–75].

Time is Brain: The Need to Treat Stroke Victims Fast

We all agree that there is a critical need for new neuroprotective or cytoprotective strategies to treat AIS to reduce morbidity, improve the quality of life (QOL) for stroke victims, and also reduce mortality. Until recently, stroke has been described as the fourth leading cause of mortality and leading cause of adult morbidity in the USA [76, 77]. It is estimated that annually, approximately 0.8 million people suffer a stroke in the USA [76, 77] and 15 million people worldwide [78]. However, since as updated definition of stroke from the American Heart Association (AHA)/American Stroke Association (ASA) [79] now includes “central nervous system infarction of brain, spinal cord or retinal cell death attributable to ischemia” and ischemic stroke with infarction with symptoms, the prevalence of stroke in society may increase. The authors also indicate that silent infarcts, which are not overtly symptomatic, are included as statistics of cerebrovascular disease. If silent infarcts are included, then 15–20 % of the population would have cerebrovascular disease that must be addressed, in particular because silent infarcts are directly correlated with cognitive impairment, dementia, and Alzheimer’s disease [79]. With a 2013 worldwide population of 7,186,451,126 [80], the estimated population with cerebrovascular disease escalates to 1.4 billon.

Time is brain is not only a well-known phrase, but it is based upon calculations reviewed by Saver [81], and reiterated by Holscher et al. [50]. Basically, every minute following an ischemic event, such as large or small vessel occlusion, 2 × 106 neurons die per minute and 14 × 109 synapses are lost, with an estimated 130 × 109 neurons in the human brain, 22 × 106 in the forebrain, representing 0.00153–0.0169 % of neurons in the human brain. Within the current DTN for rt-PA, it can be estimated that a stroke patient loses 120 × 106 neurons if treated within 60 min. To put this neuronal loss into perspective, the recent SAINT trial used a mean time to treatment of 3.76 h [19, 20] (7.52 million neurons) and the NEST trial (16 h or 32 million neurons) [27–29, 82]. Clearly, we should strive to provide patients with a neuroprotective therapy that can be administered a soon as possible after confirmation of a stroke, and if possible, it should not be dependent upon the type of stroke with which the patient presents. Why wait to treat?

Neuroprotective Drug Research and Development

Despite the lack of efficacy of select neuroprotective molecules that have been tested in modern stroke clinical trials [37], significant research advances have been made using preclinical and translational models [1, 4, 8, 9, 39, 83–85]. Using a variety of transient or permanent rodent, rabbit, and primate ischemia models that in some way recapitulate one or more of the processes involved in ischemia-induced neurodegeneration and clinical deficits, my fellow stroke researchers have become expert at developing neuroprotective molecules that can be utilized to treat stroke [1, 4, 8, 9, 39, 83–85]. Why have these advances been misused or not used at all? The answer lies within the basic design of recent clinical trials.

For years, we have been attempting to increase the therapeutic window for drugs because the infrastructure to treat patients quickly was not established. This is not only true for unproven experimental neuroprotectants, which predominantly are single-target drugs [37], but also for thrombolytics [52] and devices [29, 82]. This has universally led to the failure of all approaches except FDA-approved rt-PA [30]. With the development and implementation of the FAST-MAG approach and RSMP, we now have the opportunity to rapidly treat patients within the golden hour before there is extensive neuronal loss. Moreover, since recent research has proposed that pleiotropic agents may be required to treat stroke [3, 86, 87] in order to provide protection to the neurovascular unit [12, 51, 88], block multiple pathways of the ischemic cascade and possibly even activate trophic support mechanisms or provide neurotrophic support for recovery and regeneration, we have some insight into drug classes that may be most effective. Theoretically, all neuroprotectant drug candidates could be used immediately following patient presentation to offer the best chance of success. Since it is rational to provide neuroprotection as soon as possible, during the hyperacute phase [89], initial trials should attempt to do so.

Conclusions

The Future of Translational Stroke Research is Now!

The pieces of the puzzle described in the article are slowly coming together, but must be fully assembled both nationally and internationally, so that we have a reasonable approach to treating stroke victims worldwide. Even though this may not guarantee success, it will increase the probability that patients will be provided an option that could increase QOL. Using established networks with functional and validated diagnostic screens, prepared and trained EMS staff, and mobile informed consent, the goal of efficacious neuroprotection in stroke patients can be achieved. Since the goal is protection of the neurovascular unit as a whole, an efficacious lipophilic compound with blood–brain barrier (BBB) penetrating capability would be advantageous to target all cell types at risk of degeneration following an ischemic event. It is clear that neuronal loss is greater as time to treatment is delayed, so acute treatment with short DTN is highly recommended. This could eventually match the DTN guidelines for rt-PA of 60 min or less.