New compound could improve stroke patient recovery

The small-molecule compound, called edonerpic maleate, was developed by a research team led by Yokohama City University and Toyama Chemical Co., Ltd. in Japan. When administered to rodents and monkeys undergoing rehabilitation for brain damage, both groups of animals showed greater and faster recovery of motor function than those with just rehabilitation alone.

Toyama Chemical has already completed a clinical trial for the drug in healthy people, and plans to next conduct a clinical trial with stroke patients. The Phase 2 trial is expected to evaluate the drug's safety and ability to accelerate rehabilitation in humans. The drug must complete three phases of successful trials before it can be approved as a medication.

More than 17 million people worldwide suffer from strokes each year. The majority of strokes block blood flow to the brain, which can lead to severe paralysis. Loss of function depends on the size and location of the affected area. Some available treatments are limited to the few hours following a stroke. Long-term treatment often involves different types of physical therapy, and motor function recovery varies from patient to patient.

In this new study, the researchers describe how edonerpic maleate helps accelerate recovery of motor function. For example, macaque monkeys doing physical therapy and receiving edonerpic maleate were able to pinch small food with their fingers within a month of starting treatment. Recovery of such fine motor movements is often difficult for stroke patients.

"I hope this drug will help a lot of patients who suffer from paralysis after stroke," said Professor Takuya Takahashi, of Yokohama City University Graduate School of Medicine, who led the research.

Notably, the small-molecule compound shows positive results even when treatment started a month after the induction of brain damage - not just hours. This has the potential to boost recovery prospects for many stroke patients.

The compound appears to work in tandem with rehabilitation to enhance neural plasticity. Neural plasticity is the brain's ability to learn and adapt in response to experience. Brain cells affected by stroke cease to function normally within seconds of the trauma. However, the brain can create new pathways between neurons with external stimuli, in this case, physical rehabilitation - this is the essence of neural plasticity.

Edonerpic maleate helps this process by facilitating the delivery of an important neurotransmitter receptor, called AMPA receptor, to the structures called synapses, which mediate information between neurons. The AMPA receptors are very important for signal transmission and information processing. They receive signals from glutamate, a major neurotransmitter, and help transmit the glutamate signal to the next neuron. By helping build up AMPA receptors at synapses in conjunction with rehabilitative training, edonerpic maleate helps increase the potential for a signal transmission and neuron response.

The researchers further determined that edonerpic maleate works by binding to an intracellular protein called collapsin-response-mediator-protein 2 (CRMP2), which is related to synaptic plasticity. Mice lacking CRMP2 protein did not show an increase in AMPA receptors nor recovery of motor function, even with edonerpic maleate, indicating that CRMP2 is critical for the compound to work.

The research was done in collaboration with Japan's National Institute of Advanced Industrial Science and Technology, and the National Institutes of Biomedical Innovation, Health, and Nutrition.

Journal Reference: Abe, H. et al. "CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage." Science April 6, 2018 Vol. 360, Issue 6384, pp. 50-57 DOI: 10.1126/science.aao2300

Media Contacts:Makoto WatanabeSupervisor, Research Planning and University-Industry Cooperation DivisionYokohama City UniversityE-Mail: [email protected]^[1]

Toyama Chemical Co., Ltd.General Affairs and Personnel DepartmentE-Mail: [email protected]^[2]

About Yokohama City University:Located in the international city of Yokohama, Yokohama City University has 4 campuses, 3 faculties, 5 graduate schools, 2 affiliated research centers, and 2 affiliated hospitals that serve as the bases for education, research, and medical care. Specifically, medical science research is led by the Advanced Medical Research Center. Additional information about Yokohama City University is available through its website at: https://www.yokohama-cu.ac.jp/en/^[3]

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References

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