July 7, 2020
National Institutes for Quantum and Radiological Science and Technology
Primate Research Institute, Kyoto University
Keio University School of Medicine
Japan Agency for Medical Research and Development
A joint research group from the National Institutes for Quantum and Radiological Science and Technology (QST; Toshio Hirano, President), the Department of Functional Brain Imaging at the National Institute of Radiological Sciences, Quantum Medical Science Directorate (Takafumi Minamimoto, Group Leader); the Primate Research Institute, Kyoto University (Takakazu Yumoto, Director); the University of North Carolina (USA); the Icahn School of Medicine at Mount Sinai (USA); and the Keio University School of Medicine (Jin Nakahara, Professor, Department of Neurology) has developed DCZ, a candidate for an artificial receptor agonist with significantly improved performance and safety over existing drugs.
Brain functions such as memory and decision-making are generated by the activity of many responsible neurons. Dysfunction in neuronal activity can cause various symptoms seen in psychiatric and neurological disorders. To understand brain function and diseases, a technique is used that involves introducing artificial receptors that act as "switches" into the neurons of laboratory animals and administering a drug (agonist) that acts only on these artificial receptors to turn the activity of specific neurons on or off. However, the typical agonists used in this technique have raised concerns about their efficacy and safety, as they take a long time to take effect and can cause harmful effects (side effects) by acting on non-target receptors. Therefore, there was an urgent need to develop a new agonist that overcomes these challenges.
The development of this artificial receptor agonist, DCZ, now makes it possible to safely and rapidly flip the "switches" of target neurons with about 1/100th the dose of existing agonists. Furthermore, the researchers succeeded for the first time in the world in repeatedly turning "off" memory by introducing "switches" into neurons in the prefrontal cortex of monkeys, which is responsible for memory, and administering DCZ.
Since the effectiveness of these research results has been confirmed in mice, a typical laboratory animal, and in monkeys, which are important for pre-clinical trials before application to humans, it is expected to greatly contribute to future basic research on brain function and psychiatric and neurological disorders. The significance from the perspective of clinical application is also extremely large. For example, in the treatment of epilepsy, a potential application would be to introduce "switches" only into the neurons causing abnormal excitation and administer DCZ immediately when symptoms begin, thereby alleviating them quickly and without side effects.
This research was conducted in part using the results from programs such as the Japan Agency for Medical Research and Development (AMED) "Strategic Research Program for Brain Sciences" and JSPS KAKENHI Grant Number JP15H05917, Grant-in-Aid for Scientific Research on Innovative Areas "Pluralistic-Qualia," and was published in the online edition of *Nature Neuroscience* on July 7, 2020 (Tuesday), at 0:00 (JST).
Please see below for the full press release.