Research ArticleStroke

An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke

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Science Translational Medicine  09 Jun 2021:
Vol. 13, Issue 597, eabb6716
DOI: 10.1126/scitranslmed.abb6716

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A peptide for two strokes

Ischemic stroke and hemorrhagic stroke require different therapies. Unfortunately, the time required to identify the stroke subtype reduces the effectiveness of subsequent therapies. Toll-like receptor 4 (TLR4) signaling has been implicated in the pathophysiology of both types of stroke. Here, Fang et al. developed a peptide called Tat-CIRP able to inhibit TLR4 signaling by interfering with its accessory protein myeloid differentiation 2 (MD2). Tat-CIRP exerted neuroprotective effects in models of hemorrhagic and ischemic stroke in mice and reduced infarct volume in nonhuman primates without signs of toxicity. The results suggest that Tat-CIRP could be effective for treating both ischemic and hemorrhagic stroke subtypes.

Abstract

Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly increased in cortical neurons after stroke. We synthesized a small peptide, Trans-trans-activating (Tat)–cold-inducible RNA binding protein (Tat-CIRP), which perturbed the function of MD2 and strongly protected neurons against excitotoxic injury in vitro. In addition, systemic administration of Tat-CIRP or genetic deletion of MD2 induced robust neuroprotection against ischemic and hemorrhagic stroke in mice. Tat-CIRP reduced the brain infarct volume and preserved neurological function in rhesus monkeys 30 days after ischemic stroke. Tat-CIRP efficiently crossed the blood-brain barrier and showed a wide therapeutic index for stroke because no toxicity was detected when high doses were administered to the mice. Furthermore, we demonstrated that MD2 elicited neuronal apoptosis and necroptosis via a TLR4-independent, Sam68-related cascade. In summary, Tat-CIRP provides robust neuroprotection against stroke in rodents and gyrencephalic nonhuman primates. Further efforts should be made to translate these findings to treat both ischemic and hemorrhagic stroke in patients.

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