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Drug Discovery
Identification of a Novel Compound that Boosts the Rehabilitation Effects after Stroke
Clinical Trials to Be Conducted for a Novel Drug Approval
—Published in Science—

April 4, 2018

 A research group led by Professor Takuya Takahashi, Department of Physiology, Yokohama City University Graduate School of Medicine and Toyama Chemical Co., Ltd. of the Fujifilm Group has identified a new drug candidate that boosts the rehabilitation effects after stroke in collaboration with the National Institute of Advanced Industrial Science and Technology and the National Institutes of Biomedical Innovation, Health, and Nutrition. Aiming for a novel drug approval, Toyama Chemical will conduct a clinical trial with post-stroke patients undergoing rehabilitation therapy.

Key Points of the Research Results
・ Edonerpic*1, a compound discovered by Toyama Chemical, enhances neural plasticity, that is the fundamental mechanism of motor function recovery after brain damage.
・ Enhanced effects of rehabilitation (motor function recovery) by post-injury administration of edonerpic maleate was demonstrated in rodent and primate models.

Research Background and History
 300,000 people suffer from strokes in Japan each year, and 17 million people globally, leading to severe paralysis and compromise of patients’ quality of life. Therapies for post-stroke recovery of motor function mainly involve rehabilitation with steady training. However, the effects are limited, and more effective intervention is required.
 Neural plasticity, an alteration of neural circuits in response to external stimuli such as rehabilitation, underlies motor function recovery after brain damage. Neural plasticity induces an increase (or a decrease) of responses to neurotransmitter at synapses*2, which convey information from one neuron to another.
 AMPA receptor is a receptor for glutamate, a major neurotransmitter in the brain. Previous research by Professor Takuya Takahashi et al., of Yokohama City University as well as other research groups revealed that neural plasticity induced by learning drives trafficking and addition of AMPA receptors*3 into the post synaptic membrane, leading to the strengthening of synaptic responses, which has been widely accepted as a mechanism of neural plasticity (Reference).

Content of the Research
 Using virus-mediated in vivo gene transfer*4 and electrophysiological analysis*5, this research group demonstrated that edonerpic maleate facilitates synaptic AMPA receptor delivery (thus, enhances neural plasticity) that depends on external stimuli. The research group also revealed that the target of edonerpic maleate for this effect is a protein called CRMP2*6. Further, the research group proved that edonerpic maleate-induced facilitation of neural plasticity leads to the acceleration of motor function recovery after brain damage in a training-dependent manner in rodents and non-human primates.

 First, the research group developed a method to evaluate forelimb function in mouse brain injury model, and revealed that motor function recovery was facilitated by the administration of edonerpic maleate in a rehabilitative training-dependent fashion. (Figure 1).

 Furthermore, the research group used macaca monkeys to evaluate their human-like finger movements (to pinch an object). The research group induced brain hemorrhage in macaca monkey and demonstrated that the fine movements of the fingers is recovered by the administration of edonerpic maleate in combination with rehabilitation (Figure 2). The effect of current therapy with rehabilitation is often difficult to restore the fine finger movements which severely restrict patient’s quality of life.

These results demonstrated that edonerpic maleate is a promising drug that enhances rehabilitation effects in the recovery phase after a stroke.

Next Steps
 The group aims to deliver edonerpic maleate as a novel drug which enhances rehabilitation effects by facilitating neural plasticity to post-stroke patients suffering from paralysis as soon as possible. Toyama Chemical will conduct a Phase 2 clinical trial with patients undergoing rehabilitation in the recovery phase after a stroke. In this study, the effect as an accelerator of rehabilitation and safety of edonerpic maleate will be evaluated in human stroke-patients by objective measures in addition to conventional scales based on clinical symptoms.

*1 edonerpic: A compound developed by Toyama Chemical Co., Ltd., a member of the Fujifilm Group. Tolerability of the compound in healthy volunteers was verified in the clinical trials targeting Alzheimer’s disease.

*2 Synapse: A structure which conveys information from one neuron to the other neuron. Upon stimulation of one neuron, the information is mediated by neurotransmitter which is released from presynaptic terminal of the neuron and binds to its receptors in the other neuron, leading to the responses of postsynaptic neurons.

*3 AMPA receptor: One of the receptors for glutamate (a major neurotransmitter for the brain information processing). AMPA receptor forms ion channel in the synaptic membrane. Ion-influx through the receptor induced by the binding of glutamate contributes to postsynaptic response. Increase of AMPA receptors in the postsynaptic membrane results in the potentiation of postsynaptic response that is a central mechanism of information processing in the brain such as memory and learning.

*4 In vivo gene transfer: A method to express exogenous proteins by introducing genes into living animal. This research demonstrated the importance of AMPA receptor for motor function recovery after brain injury by virus-mediated expression of a protein that inhibits AMPA receptor function in the brains of mice.

*5 Electrophysiological analysis: A method to evaluate the communication between neurons by measuring the electric signals generated in neuron. By changing the experimental conditions, electric signals specific to AMPA receptors can be evaluated.

*6 CRMP2 (Collapsin-Response-Mediator-Protein2): A molecule that inhibits axonal growth. Recent research suggests its involvement in the neural plasticity.

Published Papers
*This research will be published in the scientific journal Science. (Online as of April 5, 2pm U.S. EDT: April 6, 3am Japan Time)

*This research was conducted with grants from the Ministry of Education, Culture, Sports, Science and Technology “Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program,” the Japan Agency for Medical Research and Development (AMED) “Strategic Research Program for Brain Sciences (SRPBS),” and “Brain Mapping by Integrated Neurotechnologies for Disease Studies.”

Experience strengthening transmission by driving AMPA receptors into synapses
Takahashi et al. Science. 2003 Mar 7;299(5612):1585-8

Synaptic AMPA receptor plasticity and behavior
Kessels and Malinow. Neuron. 2009 Feb 12;61(3):340-50

Serotonin mediates cross-modal reorganization of cortical circuits
Jitsuki et al. Neuron. 2011 Feb 24;69(4):780-92

Contextual learning requires synaptic AMPA receptor delivery in the hippocampus
Mitsushima et al. PNAS July 26, 2011. 108 (30) 12503-12508

A cholinergic trigger drives learning-induced plasticity at hippocampal synapses
Mitsushima et al. Nature Communications, volume 4, Article number: 2760 (2013)

Optical inactivation of synaptic AMPA receptors erases fear memory
Takemoto et al. Nature Biotechnology, volume 35, pages 38–47 (2017)

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