Ischemic stroke occurs when a blood vessel in the brain is blocked whereas hemorrhagic stroke occurs when a blood vessel in the brain breaks. Essentially opposite in outcome, ischemic stroke results in restricting blood flow to the brain while hemorrhagic stroke results in bleeding into the brain tissue.

These major types of strokes occur in 17 million patients worldwide each year and together account for more than 10% of all deaths, resulting in an enormous burden for healthcare systems and caregivers.

There is a tiny window of about 4.5 hours, within which if clot-breaking or thrombolytic medications can be administered in the case of ischemic stroke, the loss of brain tissue can be restricted and the chances of the patient returning to a near normal lifestyle are favorable.

Before these life-saving drugs—which consist of a combination of the clot dissolving alteplase and tenecteplase—can be administered however, magnetic resonance imaging (MRI) must be performed to distinguish ischemic from hemorrhagic stroke. This delays treatment and reduces the chances of recovery.

A new animal model study circumvents this time-consuming need for neuroimaging before treatment can be administered in stroke patients, by designing a synthetic peptide that targets a common and critical component in both ischemic and hemorrhagic strokes.

The study is reported in the journal Science Translational Medicine, in an article titled “An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke” and is led by senior investigators Xunming Ji, PhD, at the Capital Medical University in Beijing, and Hailong Dong, PhD, and Lize Xiong, PhD, at the Fourth Military Medical University in Shaanxi, China.

Synthetic peptide
TAT-CIRP (TC) protects the brains of mice and reduced the loss of brain tissue 28 days after hemorrhagic stroke compared to saline [Z. Fang et al, Science Translational medicine, 2021]
The authors first show the expression of myeloid differentiation protein 2 (MD2), which was earlier believed to be expressed solely in microglia in the normal brain, is markedly enhanced in neurons of the cerebral cortex after a stroke. MD2, the authors show, elicits programmed cell death in neurons through two independent pathways.

They then designed a synthetic peptide—trans-trans-activating cold-inducible RNA binding protein, Tat-CIRP—that protects cultured neurons in vitro against toxicity due to hyperexcitation, by disrupting the function of MD2.

MD2 (myeloid differentiation protein 2) elicits programmed cell death in neurons through two independent pathways. [Source: Z. Fang et al, Science Translational medicine, 2021]
The researchers then recapitulate the neuroprotective effect against ischemic and hemorrhagic stroke in mice in two separate ways—by injecting mice with Tat-CIRP and by deleting the MD2 gene.

Moving on to a larger model organism, the rhesus monkey, the scientists show Tat-CIRP injection reduces the volume of dead brain tissue and preserves neurological function 30 days after ischemic stroke.

Through this evidence the scientists demonstrate that Tat-CIRP can cross the blood-brain barrier, and is safe as high doses of the peptide administered in mice show no toxicity. Tat-CIRP safely stops neuronal loss and reduces the loss of brain tissue in mice and nonhuman primate models of ischemic and hemorrhagic stroke, even when administered 6 hours after the stroke.

The authors conclude, “Our current study suggests that Tat-CIRP is a promising neuroprotectant against both ischemic and hemorrhagic stroke and might not require a neuroimaging diagnosis before its use. These results warrant studies on the translation of Tat-CIRP for the treatment of both ischemic and hemorrhagic stroke in humans.”

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