"Pathway Causing Neuronal Death After Stroke Identified"... From Revealing the Cause to Therapeutic Clues [Reading Science]

The key pathway leading to the sequential death of neurons after a stroke has been identified by a Korean research team. This translational research achievement, spanning from basic research to verification of a novel drug candidate, was published on April 28 (Korea Standard Time) in the international journal "Cell Metabolism."

The Institute for Basic Science (IBS) announced that the research team led by Changjoon Lee, head of the Memory and Glia Research Center, along with their collaborators from Eulji University, has identified that hydrogen peroxide (H₂O₂), which is excessively produced during ischemic stroke, stimulates astrocytes to generate collagen, and this process leads to neuronal cell death.

Complete Recovery of Motor Function in Stroke Monkeys After Administration of KDS12025. When the research team administered the novel drug candidate KDS12025 to a stroke monkey model, motor impairments were completely restored within one week. In an experiment where monkeys had to pick up fruit, the stroke monkeys could not move due to motor impairments, but the monkeys treated with KDS12025 succeeded all 10 times. Provided by the research team

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Stroke is a major severe disease that occurs when a cerebral blood vessel is blocked or ruptures. Even after the initial damage, neuronal cells continue to die, which exacerbates aftereffects. Until now, astrocytes were known for forming a 'glial scar' that protects the damaged area, but it had not been clearly demonstrated that this barrier could actually induce neuronal cell death.

The research team focused on the sharp increase in hydrogen peroxide, a type of reactive oxygen species, immediately after a stroke, and how this signal stimulates astrocytes. Stimulated astrocytes produce type I collagen, and the accumulation of this collagen forms a glial barrier that surrounds neurons and induces their death. In other words, the pathological pathway of 'hydrogen peroxide → collagen production → neuronal cell death' has been confirmed.

A schematic diagram of type 1 collagen production by astrocytes and neuronal cell death in ischemic stroke. Following ischemic injury, astrocytes are activated by increased hydrogen peroxide and produce collagen, which induces neuronal cell death. The research team confirmed in a primate model that removing hydrogen peroxide or inhibiting collagen production can alleviate neuronal damage and motor dysfunction. Provided by the research team

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The researchers also verified whether blocking this pathway would provide therapeutic effects. When the novel drug candidate 'KDS12025,' developed in-house, was administered to a mouse model, both collagen production and neuronal cell death were significantly reduced, and impaired motor function improved. Notably, functional improvement was observed even when the drug was administered after some time had passed since the onset of stroke, suggesting that the therapeutic intervention window could be expanded.

Similar results were observed in a primate model. Subjects that received the compound showed a reduction in lesion size and recovery of previously paralyzed hand functions, indicating the potential for improvement in motor function. However, the research team explained that as these are preclinical results, further validation is needed before clinical application can be considered.

Boyeong Lee, IBS research fellow and co-corresponding author, said, "We have elucidated at the molecular level the mechanism by which collagen is produced in astrocytes in response to reactive oxygen species. This offers important clues not only for stroke but also for research into neurodegenerative diseases such as dementia and Parkinson's disease." Seungjun Yoo, professor at Eulji University and co-corresponding author, stated, "As we have verified the therapeutic effect in a primate model, there is a possibility that this may lead to clinical research in the future."

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