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New knowledge about the way antidepressants are bound in the brain’s nerve cells

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Published Monday 08 February 2010 | Julie Schmøkel

Aarhus researchers apply new precision in determining the way antidepressant medications work.
These discoveries provide hope for developing improved antidepressant medications for the approximately 200,000 Danes who suffer from depression.

The new research results have been published in the internationally acknowledged scientific journals Journal of the American Chemical Society and Journal of Biological Chemistry.

 

Fact: How does antidepressant medication work?

Antidepressants work by increasing the amount of the signal substance serotonin in the space between the nerve cells in the brain.

As a link in the communication between the nerve cells, these continuously release serotonin from the cells to “reuptake” it shortly afterwards. A protein in the nerve cell walls acts as a pump and ensures this reuptake.

Antidepressants work by blocking these proteins. However, exactly where and how this takes place has not been known to date.

Aarhus researchers describe how antidepressants are bound in the nerve cells

In the world of researchers, there has been disagreement about the way in which antidepressants bind to the protein in the nerve cell wall that transports serotonin into the nerve cell. This is what the Aarhus researchers have now determined.

They have also developed and experimentally validated a precise model of the structure of the molecules in the pump – i.e. of the protein in the nerve cell wall that transports serotonin into the nerve cell.

The researchers now know exactly how different types of antidepressants bind and orient themselves spatially in the pump protein in the nerve cell wall when they stop the transport of serotonin into the nerve cell.

See details in the two figures and captions.

Hope for improved treatment of patients with depression

It is crucial for the development of better antidepressants that researchers and the pharmaceutical industry have precise knowledge about the molecular processes between such medication and the transport protein.

  • “Our discoveries are crucially important in this context,” says Steffen Sinning from Aarhus University Hospital in Risskov, and continues:
  • “Our new research results consist of basic research that can enormously benefit the pharmaceutical industry. We are therefore making the new knowledge freely available for researchers and the pharmaceutical industry all over the world.”

Not only are the new results ground-breaking basic research in themselves, but they also provide an opportunity for the researchers to find unexploited options for improving the existing medicine. This inspires hope for designing new antidepressants that are more effective, have fewer side effects, and act more rapidly.

Results made possible via interdisciplinary collaboration

The new research results were achieved in productive interdisciplinary collaboration between three specialist research groups in Aarhus.

The three groups come from the Department of Chemistry at Aarhus University and the Aarhus University Hospital in Risskov, and their fields of research are:

  • Biomodelling (Department of Chemistry): the researchers use computer simulations to make theoretical 3D models of the molecules.
  • Organic synthesis (Department of Chemistry): the researchers produce substances in the laboratory that are related to existing antidepressant medication.
  • Molecular neurobiology (Aarhus University Hospital in Risskov): the researchers study the molecular mechanisms underlying the binding of the antidepressant to the transport proteins in the nerve cells.

The three research groups achieved their results by making theoretical computer-calculated models for the binding of the antidepressant to the transport protein. They subsequently made variants of the existing types of antidepressants and, by testing these on different variants of the transport protein in cell cultures in the laboratory, they were able to determine which of the theoretical computer-calculated models were the right ones. The researchers thereby achieved a detailed picture of the orientation of antidepressants in the transport protein, and thus how they are able to block it.

  • “The theoretical and the experimental research thereby support and complement each other, and the conclusions are therefore stronger than the sum of the individual contributions of our three groups,” says Henrik Helligsø Jensen from the Department of Chemistry.

Figure 1

Communication between nerve cells

The signals in our nervous system run through the nerves as electrical signals, but the signal from one nerve cell to another is transmitted by signal substances such as serotonin.

When the electrical signal reaches the end of the nerve cell, this makes it release the substance serotonin (the orange spheres) in the space between the two nerve cells. The serotonin now diffuses to the neighbouring nerve and binds to a receptor here. This releases an electrical impulse that then continues to run through the next nerve cell, etc.

The first nerve cell can “reuptake” the serotonin by means of transport proteins (the green tube) in the nerve cell wall.

How antidepressants work

Antidepressants work by blocking the transport protein (the green tube to the right) and the amount of serotonin is thus increased between the nerve cells. This provides patients with relief from their symptoms of depression.

Figure 2

This illustration demonstrates how the antidepressant medications escitalopram (Cipralex®) and imipramine (Imipramin®) – to the left and right, respectively – are both centrally bound in the transport protein for the signal substance serotonin.

By combining computer-based biomodelling, organic chemical synthesis and molecular neurobiology, the researchers have identified the orientation of the antidepressants in the transport protein.

At the bottom is a simplified version of how the antidepressants are bound. This only shows that part of the transport protein that is in immediate proximity and is thereby crucial for how the antidepressant blocks the transport of serotonin in the nerve cells and how strongly it does so.



Fact box 1

The new discoveries provide hope for improving the existing antidepressant medications.

There are enormous human and socio-economic costs involved with more and more people developing depression. This is an invalidating disease, both commercially and socially, and it can lead to suicide.

At least one in every five Danes can expect to have a depression at some stage of their lives and the UN’s World Health Organization (WHO) expects depression to be the second most expensive of all diseases for society by 2020. Effective treatment of depression is therefore crucial for depressed patients, their relatives, and for society in general.

Treatment is made difficult with current medication because it usually takes 3–5 weeks from the time a patient commences treatment until the antidepressants take effect. In addition, current antidepressant medications have no effect on approximately one third of the population.

 

 

Fact box 2

Serotonin is produced in areas including certain parts of the brain, where it acts as a signal substance between nerve cells. This communication is known to play a role in depression.

The signalling is affected by the type of antidepressants called SSRI preparations (selective serotonin reuptake inhibitors) and TCA preparations (tricyclic antidepressants). These are substances such as escitalopram, clomipramine and imipramine, which are marketed in Denmark under the trade names Cipralex® Anafranil® and Imipramin®.

Photo of the researchers responsible for the new knowledge

The researchers behind the new knowledge about the way antidepressants are bound in the brain’s nerve cells are seen here in front of the Aarhus University Hospital in Risskov.

Back row from left: Steffen Sinning, Marie Jensen, Maria Musgaard.
Front row from left: Henrik Helligsø Jensen, Kasper Severinsen, Birgit Schiøtt, Ove Wiborg.
Not included in the photo: Heidi Koldsø, Thuy Tien Tran, Leyla Celik, Tine Meyer and Mikael Bols.

More information

The new research results have been published in two internationally acknowledged scientific journals:

Comments on content: Julie Schmøkel
Revised: 25.02.2010