KOKI-Richter joint success: results of a team led by Professor Vizi in the British Journal of Pharmacology

To be the author of a paper in a leading international journal, owned by the British Pharmacological Society, that publishes high-quality research in any area of experimental pharmacology is itself a commendable achievement. Our former President of the Academy, Professor Emeritus E. Szilveszter Vizi is one of the few people to be an Honorary Fellow of the  British Pharmacological Society and this is the seventeenth time he has been an author in its highly prestigious journal. However, he is as proud as the first author of the article, postdoctoral researcher Pál Tod, whose results were accepted for publication in the British Journal of Pharmacology for the first time.

Professor Vizi and postdoctoral researcher Pál Tod were interviewed about the work.  

Sylvester E. Vizi

- A very unpleasant side effect of third-generation antipsychotics used to treat schizophrenia and major depression is the development of involuntary hyperkinetic movement disorders, which make the patient's social integration significantly more difficult. The US FDA has already approved the use of VMAT-2 (vesicular monoamine transporter 2 inhibitor) tetrabenazine and its derivatives in March 2018, which can be used to attenuate and inhibit this side effect. There are reliable clinical data on this, but how this type of compound acts in different brain areas is not known. In a paper published in the leading journal of pharmacology, the British Journal of Pharmacology, first authored by Paul Tod and colleagues at Richter, we were the first to clarify this question. Among the third generation of antipsychotics, one of the most successful drugs is Richter's cariprazine (Vraylar), which is marketed in North America by AbbVie, the world's third pharmaceutical company. Its sales generate about $3.5 billion a year, of which Richter, as the patent holder, receives a substantial share. The drug we studied is used to treat hyperkinetic syndrome induced by the aforementioned antipsychotics.   

- As well as the importance of knowing where and how a compound works, what other benefits can be derived from the results we have just obtained?

- Among other things, it could help design new compounds that could be very useful in the treatment of schizophrenia and depression.

 - Are there any other significant benefits from this very successful work?

- Our recent experiments have provided further evidence for our discovery, more than forty years old, in collaboration with Professor WDM Paton (Oxford), of non-synaptic signaling, which suggests that neurotransmitter release is not only and exclusively from the synapses of the nerve cell, but can also occur from the cell.

- What do we know about tetrabenazine?    

Pal Tod 

- The hyperkinetic movement disorders described by the Professor are caused by a loss of inhibitory function in different brain areas. Since drugs of the tetrabenazine type inhibit the uptake of essential monoamines (noradrenaline, dopamine, serotonin) released from nerve cells into vesicles during electrical stimulation, we investigated the effect of tetrabenazine on the release of these neurotransmitters from nerve cells and their storage. This was also motivated by the fact that one of the main side effects of tetrabenazine-based drugs is, in turn, the development of depressed mood and depression.

- What was the simplest and most reliable way to investigate this? 

- The so-called "release method", which measures the release of radioactively labeled signal transducers from brain slices in response to digital (neuronal stimulation) and analogue (cytoplasmic transporter reversal) stimuli. 

The great advantage of this method is that it can be used to study not only groups of cells but also larger brain areas. This is also important because neurons do not function in isolation, their interactions with each other and their environment cannot be neglected, so measuring from brain slices more accurately models the effects of tetrabenazine and their derivatives in the living organism than, for example, a cell-culture of neurons. It also provides a clear answer to how tetrabenazine affects the release and storage of monoamines. We have shown that these compounds can be used to inhibit the release of monoamine and monoamine-containing proteins without affecting the u.n. "uptake" of released transmitters back to the terminal (SSRI-type antidepressants have an effect anyway) can be inhibited by these compounds. Furthermore, we have also shown that the cholinergic vesicle transporter, which shares 40% structural homology with the monoamine transporter, is not inhibited by these compounds. 

Thus, a brain model can be created in which monoaminergic digital transmission is significantly inhibited, but cholinergic transmission is fully intact, possibly even increased. With such neural connections, Dr. Lendvai and I found that dopamine can be released from the cytoplasm in amounts that alter animal behavior.  

- What other experiments were needed to confirm and complement these results?

- It was also necessary to demonstrate this in live animals. This was done at Richter Gedeon with the help of Dr Balázs Lendvai - another student of Professor Vizi - and his research team (Viktor Román, Anita Varga, and Roland Pálkovács).  In the experiment, a hyperkinetic movement disorder was induced by the psychoactive drug MDMA (ecstasy), which releases dopamine from the endocrine plasma of the terminal apparatus, which was not inhibited by tetrabenazine treatment, demonstrating that the vesicular transmitter release associated with stimulation is not the only condition for behavioral changes. An analogous form of chemical signaling has been partially demonstrated in previous work.

- Is this experimental setup applicable only to the study of tetrabenazine?

- No way. It can also be used for rapid testing of other drug molecules designed for similar purposes and for comparison with tetrabenazine derivatives. Our experiments in live animals can also be used to monitor the potential side effects of new drugs. Thus, drug molecules that are then designed and developed for the treatment of hyperkinetic movement disorders can enter clinical trials after more careful testing.

- How would you briefly summarise your main achievements?

 - We have succeeded in providing neurochemical evidence to explain the brain mechanism of tetrabenazine and related agents (VMAT-2) inhibitors, as well as the role of dopaminergic and noradrenergic transmission in hyperkinetic movement disorders.