A new era for stroke therapy: Integrating neurovascular protection with optimal reperfusion

Abstract

Recent advances in stroke reperfusion therapies have led to remarkable improvement in clinical outcomes, but many patients remain severely disabled, due in part to the lack of effective neuroprotective strategies. In this review, we show that 95% of published preclinical studies on "neuroprotectants" (1990-2018) reported positive outcomes in animal models of ischemic stroke, while none translated to successful Phase III trials. There are many complex reasons for this failure in translational research, including that the majority of clinical trials did not test early delivery of neuroprotectants in combination with successful reperfusion. In contrast to the clinical trials, >80% of recent preclinical studies examined the neuroprotectant in animal models of transient ischemia with complete reperfusion. Furthermore, only a small fraction of preclinical studies included long-term functional assessments, aged animals of both genders, and models with stroke comorbidities. Recent clinical trials demonstrate that 70%-80% of patients treated with endovascular thrombectomy achieve successful reperfusion. These successes revive the opportunity to retest previously failed approaches, including cocktail drugs that target multiple injury phases and different cell types. It is our hope that neurovascular protectants can be retested in future stroke research studies with specific criteria outlined in this review to increase translational successes.

Keywords: Stroke; ischemia; neuroprotection; reperfusion; translational research.

Figure 1.

Flowchart of study selection. A total of 7510 studies on Pubmed and Web of Science were screened by evaluators. After exclusion for lack of relevance and various other criteria, 2489 studies were eligible for the qualitative synthesis.

Figure 2.

Neuroprotectants in preclinical models of transient and permanent ischemia. (a) Preclinical studies of ten neuroprotectants that entered Phase III clinical trials are divided into those employing permanent (pink) or transient (blue) ischemic insults. (b) Neuroprotectants with positive effects in transient models but neutral or negative effects in permanent models are listed.

Figure 3.

Neurological functional assessments in preclinical studies of neuroprotectants. (a) Only 32% of the eligible preclinical studies included measurements of neurological functional outcomes in stroke animals. Even among those that reported neurological function, fewer than 30% of studies monitored functional recovery over extended periods (defined here as >14 days). (b) Among the 85 preclinical studies on the ten neuroprotectants that entered Phase III clinical trials, only 39 measured neurological function as an endpoint, and only 12 evaluated neurological functions longer than 14 days after stroke.

Figure 4.

Aging imbalance, therapeutic targets, and publication bias in preclinical studies of ischemic stroke. (a) Out of more than 2,000 treatments, only two have been evaluated in an aged rodent model of permanent ischemia, and nine neuroprotectants have been assessed in aged rodent models of transient ischemia. (b) The potential mechanisms underlying the therapeutic properties of neuroprotectants in both transient and permanent stroke models. More than 80% of the neuroprotectants in the current analyses target inflammation, apoptosis, oxidative stress, neurotrophy, and excitotoxicity. (c) 95% of studies fitting all of our inclusion criteria reported positive outcomes in preclinical models. PISM: permanent ischemic stroke model; TISM: transient ischemic stroke model.