The case for neuregulin-1 as a clinical treatment for stroke

Abstract

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

Keywords: clinical trial; excitotoxicity; inflammation; ischemia; neuregulin; neuroprotection; oxidative stress; stroke.

Figure 1

NRG-1 activates multiple pathways through erbB receptors to inhibit inflammation and initiate neuroprotection. LPS activates the common inflammation pathway through the toll-like receptor (TLR) and canonical NFkB pathways, leading to the production of pro-inflammatory factors such as TNFα, IL-6, and IL-1. Danger-associated molecular patterns (DAMPs) activate apoptosis through Bax/Bak pathways. NRG-1 acts through erbB receptors to: (1) initiate the PI3K/Akt pathway which inhibits NFkB mediated pro-inflammatory responses, (2) activate nuclear factor kappaB-inducing kinase (NIK) which also inhibits inflammation by initiating the alternative/non-canonical NFkB pathway to produce anti-inflammatory factors such as IL-13, IL-5, and G-CSF, and (3) activate the MAPK and Akt pathways to inhibit apoptosis.

Figure 2

NRG-1 potential as a clinical treatment for stroke. Findings from our laboratory and others further indicate that NRG-1 has fulfilled many STAIR criteria that already place it in advantage over NXY-059 and comparable to nerinetide that have reached clinical trials NRG-1 has shown success in completing of the STAIR criteria where NXY-059 did not, robust neuroprotection in rodent models, blinding and randomization, extended time windows in clinically relevant stroke models and reproducibility in multiple laboratories. Nerinetide has shown some hope for neuroprotective strategies for stroke and NRG-1 is on track to similarly fulfill the STAIR criteria.