After an ischemic stroke, every minute counts to reopen the blocked artery. Once the blood returns, however, a second problem arises: the sudden resumption of flow can trigger a cascade of damage, with neuron death, massive inflammation and increased risk of lasting disability.
In this difficult context for patients and families, a team from Northwestern University is testing a new approach: a
post-stroke injection based on peptides, administered just after reperfusion. In mice, this intravenous infusion crosses the blood-brain barrier and concentrates in the injured area, with astonishing benefits.
A post-stroke injection against secondary lesions
A ischemic stroke occurs when a clot blocks a cerebral artery; approximately 80% of strokes are of this type. In France, more than 100,000 people are hospitalized each year for a stroke, often with serious after-effects. Reperfusion saves life, but the inflammatory wave that follows sometimes worsens brain damage.
The researchers used, in a preclinical study described in the journal Neurotherapeuticsa mouse model of transient occlusion of the middle cerebral artery for 60 minutes, followed by reperfusion, then a single intravenous injection of either saline or IKVAV-PA peptide. “Reducing this level of disability with a therapy that could potentially help restore function and limit damage would truly have a powerful long-term impact.“, commented Ayush Batra, neurocritical care neurologist, in an interview relayed by Northwestern University.
“Dancing molecules” that repair the brain
IKVAV-PA is an amphiphilic peptide that self-assembles into highly mobile nanofibers, sometimes referred to as “dancing molecules.” After injection, Samuel I. Stupp’s team observed that these structures crossed the blood-brain barrier at the level of the ischemic area, then were deposited mainly in the affected hemisphere, closest to the lesion.
Seven days after the experimental stroke, tissue staining showed a mean infarct volume of 26.9 ± 6.3% of the infarcted hemisphere in mice given saline, compared to 10.6 ± 2.4% on IKVAV-PA, a relative reduction of approximately 60%.
Compared to untreated mice, those treated with the “dancing molecules” had significantly less brain damage (with an average infarct volume reduced by 60%), reduced signs of inflammation and reduced signs of excessive and deleterious immune response. The weight and appearance of major organs remained similar between groups, with no obvious toxicity.
“Once the blockage occurs, harmful molecules accumulate. When the clot is suddenly removed, all of these harmful substances are released into the bloodstream, where they cause further damage.”explains Stupp. “But these mobile molecules have anti-inflammatory properties that counter these effects and, simultaneously, contribute to the repair of neuronal networks.“.
A promising advance, still far from the patient
When a doctor quickly restores blood flow to a region of a stroke patient’s brain, the permeability of the blood-brain barrier increases locally, naturally creating a transient opening and an opportunity for therapeutic intervention, Professor Batra explained. : “If we add to this a very mobile peptide which crosses the barrier more easily, we really increase the chances that the therapy will go where we want it to go.“.
However, the behavioral tests carried out in mice (neurological score, exploration of an open field) did not demonstrate any clear functional recovery at 3 and 7 days, which is reminiscent of the path remaining before clinical application. The next steps will aim for longer follow-ups, detailed cognitive evaluations and, ultimately, human trials.
But the authors are already very enthusiastic and are considering other potential applications. Prof. Stupp, co-senior author and chair professor of materials science and engineering, chemistry, medicine and biomedical engineering at Northwestern University said: “One of the most promising aspects of this study is that we were able to demonstrate that this therapeutic technology, which has shown considerable promise in the treatment of spinal cord injuries, can now be applied to a stroke model and delivered systemically. This mechanism of systemic delivery and the ability to cross the blood-brain barrier represents a major advance that could also prove useful in the treatment of head injuries and neurodegenerative diseases such as multiple sclerosis.”.