Reserchers

TOHDA Michihisa Associate Professor

TOHDA Michihisa

AffiliationLaboratory of Consilienceology for Wakan-yaku, Section of Neuromedical Science, Division of Bioscience, Department of Research and Development

Research fieldsIntegrated Pharmacology

Campus careerPh.D.

Biography Academic Research Staff

Education

Mar. 1984: Graduated from Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University
Mar. 1986: Graduated from Toyama University Graduate School of Pharmaceutical Sciences (Master degree)
Jun. 1988: Leave before graduation from Hokkaido University Graduate School of Pharmaceutical Sciences (Doctor cause)

Job career

Jun. 1988: Assistant Researcher in Faculty of Pharmaceutical Asciences, Hokkaido University
Oct. 1993: Assistant Professor in Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical UniIersity
Feb. 2005: Assocoate Professor in Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical UniIersity

Research theme

Department

Division

Section

Project

Outline of the research

Wakanyaku is simple! Wakanyaku is atractive! Wakanyaku give us newness!

Current main research themes
1. Providing evidence for the theory of Wakanyaku (Japanese oriental medicines based on the traditional medicine in China) and providing new research strategies based on it
2. Elucidation of the unique action of Wakanyaku closely linked to the biological reaction and development of ultra-low concentration drug that breaks down the measurement pharmacology
3. Classification of depression based on Wakanyaku theory, elucidation of pathogenesis, and development of new antidepressant
4.Development of a new Wakanyaku prescription that prevents "heart failure due to side effects of anticancer drugs" and "lethal myocardial infarction"

In Wakanyaku (Japanese oriental medicines based on the traditional medicine in China), the timing of taking is between meals unlike the pure drugs. In other words, it is necessary to think about Wakanyaku in terms of foods like snacks, not drugs as foreign toxic bodies. There is also a definite personality that is prescribed to humans, not to illnesses. Therefore, it may be necessary to conduct research based on a unique systematic foundation different from the modern medicine research. Fortunately, the unique academic foundation for Wakanyaku is well established in both pharmaceutical and medical perspective. These Wakanyaku conceptions include galenical natures of five factors/stages, herb pairs, specific processing, qi(ki)/blood/fluid, eight direction theory and others. By utilizing these theories in modern research, innovative viewpoints and therapeutic drugs that could not be thought of before could be born. Since, in the fundamental foundation, there is no big difference between Wakanyaku theories and modern medicinal theories (pharmacology and physiology), a small effort for mutual understanding will be thought to lead to innovative results.

The following points can be given as the individuality of Wakanyaku.
1) A very small amount of ingredients play a main role (Aroma is also an active ingredient?), and it works closely with biological effects. Many pure drugs are inhibitory and/or have blocking action. As a certain amount or more is required to make them act, side effects are likely to occur in pure drugs. On the other hand, there are no side effects with the correct use of Wakanyaku.
2) Wakanyaku Acts systemically. Even for brain diseases, there is a possibility that secondary therapeutic effects will be shown via nerve functions from the digestive system and the like. The concept of acupuncture meridians may be helpful to understans that. The brain works only when stimulated from the outside as like a conductor of orchestra who does not emit sound by itself.
3) The basic unit of Wakanyaku action is “herb pairs” which is a combination of two crude drugs; combination of an active function and an inhibitory function, combination of mutual emphasis, and others. These are not limited in Wakanyaku, but also can be seen in various biological mechanisms (ex, noradrenaline receptor subtypes and channel-forming receptors such as GABA and NMDA). The effect and effort of Wakanyaku greatly depending on the combination based on the “herb pairs” theory.
4) Because safety for humans has been established, it possible to conduct basic research (not clinical research) using humans under certain conditions followed by animal experiments. Since detailed studies of action mechanisms, effectiveness, and active ingredients can be developed by animal experiments, etc., it will be easy to maintain a correlation with clinical effects.

While keeping these points, I am conducting research using the following analytical methods.
1) In order to study the effects of drugs based on their theories, it is necessary to evaluate the combination of herbal medicines by myself. In addition, it is necessary to consider differences between lots of herbal medicines and changes in components over time. For these purposes, 3D-HPLC profile of the sample is usually taken to be maintain a chemical viewpoint that responds to changes in responsiveness rather than a quality control viewpoint. Even if it is a degradation product, when it is found by comparison correlating with activity, further research development can be started.
2) Analysis of gene expression changes in cultured cells treated with crude drugs/prescription extracts are analyzed, together with the above component analysis, and the RNA/cDNA is accumulated and used for further research. With the accumulation of various data, a new perspective is opened from it. The idea that drugs acting on the brain have no effect unless they reached into the brain is wrong. It is possible to act via the nervous system or the hormonal system, and there are actually textbook level’s of knowledge examples of corticosteroids. Experiments in which a crude drug extract is directly added into a culture medium are often rejected, but it is optimal for studying the pharmacological action of “herb pairs” at the primary action site and the mechanism of action in the cytoplasm. Time-lapse fluorescence microscope is also used conducting experiments to detect drug effects in the cells into which various sensors and genes are introduced.
3) For gene expression changes in cells treated with crude drugs and tissues of small model animals, RNA expression are analyzed using a real-time PCR device. Changes in genomic DNA using methylation analyzers and editing changes on serotonin 2C receptor (5HT2C) mRNA are also studying. Especially for the latter, editing during fetal and neural network formation and the significance of this is being examined in detail, including the discovery of new editing sites.
4) The electrophysiological response is the most elaborate to see the action response. I succeeded in isolating serotonin-acting components in herbal medicines using this system on the mRNA injected Xenopus oocytes. It is also possible to examine changes in the reactivity of the protein by mutating the injected mRNA, and I am studying the physiological effects of 5HT2C mRNA editing.
5) The effect of Hochuekkito is examined by human functional MRI (fMRI), and the prescription analysis based on the knowledge and the Wakanyaku theories is being promoted by small animal fMRI. By examining the reactivity of small animals, it can be expected that this will lead to elucidation of evidence in Kampo medicine, differences in reactivity due to differences in the composition of crude drugs, and development of new agonistic drugs. Although small animal MRI has many difficulties, if it can be solved, studies that will lead to treatment of humans relatively directly can be promoted using by Wakanyaku.
6) A small animal autonomic nervous activity analysis system (electrocardiogram, electroencephalogram, blood pressure, etc.) was introduced. In order to analyze the effects of the above-mentioned peripheral action to the brain response, I aim to capture changes in the autonomic nervous system response when Wakanyaku is refluxed in the stomach. Hochuekkito has been found to cause strong respiratory depression immediately after oral administration in anesthetized animals, and MRI has also observed a strong response in the hypothalamus. The details of the mechanism are planned to be studied using this system.

Thoughts on research

My opinion: The most important points for academic research are;
"curiosity", "observation" and "endurance".
What is this? What interesting is this! Try this a-gain.
I want to continue the adventure to the unexplored “Wakanyaku Universe”, cherishing the pure and insatiable curiosity just like a young children's mind. Fortunately, the development of analytical instruments in recent years is beginning to provide good tools for this adventure in the Universe. Wakanyaku has the most sophisticated and most advanced system that can provide inovative medical care. We do not yet deeply talk about it.
I think there are two ways for doing the scientific research. One is setting goals and made “one-team” for building the achievements, and another is starting it with curiosity, proceeding in own interesting, resulting that reached brilliant “only one” level that could not have been predicted even by oneself. A typical example of the latter is the discovery of jellyfish green fluorescent protein GFP by Dr. Shimomura. The latter research can only be done by scientist in academic belonging. Even if it is lonely on the way of studying, once obtained breakthrough results, large numbers of researcher will come together. Although, in many cases, we will reach a wandering Black Hole, I am determined without fear of that to continue studies with curiosity, observation and endurance. The most important thing for researchers in Academia is that we can say “E pur si muove” with deep insight and confidence, or “the king is naked” with pure feelings like a child.

Paper

Profiling 120 kinds of herbal extracts and their effects on morphological changes in cultured neuronal or glial cell lines followed by extracting RNA to make cDNA library: Consideration for use to studies based on the Wakanyaku theories
M. Tohda
Traditional Kampo Medicine. submitted
Single Work

Profiling 120 kinds of herbal extracts and their effects on morphological changes in cultured neuronal or glial cell lines followed by extracting RNA to make cDNA library: Consideration for use to studies based on the Wakanyaku theories
M. Tohda
Traditional Kampo Medicine. submitted

The Wakan-yaku Universe: A useful authorized traditional concept for developing novel therapeutic categories and medicinal drugs.
M. Tohda, H. Watanabe.
Biol Pharm Bull. 41, 1627-1631. 2018

Serotonin 2C receptor as a superhero: diversities and talents in the RNA universe for editing, variant, small RNA and other expected functional RNAs.
M. Tohda
J Pharmacol Sci. 126, 321-328. 2014

Serotonin 2C receptor (5-HT2CR) mRNA editing-induced down-regulation of 5-HT2CR function in Xenopus oocytes: the significance of site C editing.
M. Tohda, P.T. Hang, N. Kobayashi, K. Matsumoto.
J Pharmacol Sci. 113, 362-367. 2010

keyword

Wakan-yaku Universe, Serotonin 2C receptor (5HT2CR) , BNIP-3, RNA editing, Hochuekkito, Functional Mental Disdorer (FMD)