New depression therapy uses HIV molecules

Using a molecule from HIV, researchers at the Freiburg University Medical Centre introduced an antidepressant protein directly into nerve cells.

Active ingredient unfolds antidepressant effect through direct intervention in cells

Using a molecule from HIV, researchers at the Freiburg University Medical Centre introduced an antidepressant protein directly into nerve cells.

Antidepressants are the most commonly used psychotropic drugs. However, they often only improve the symptoms after weeks or months, which may have severe side effects or may not have any effect at all on many patients. Scientists from Freiburg’s University Medical Centre are working on a new therapeutic approach in a mouse model that could largely solve this problem: They coupled the therapeutically active signaling protein Homer1a with a “smuggler” molecule that enables the HI virus to enter the cells. This permits the drug to enter the nerve cell and directly intervene in the cell’s signaling pathways.

"The drug develops its antidepressant effect without any detours and is therefore much faster and stronger than classical antidepressants," said Dr. Tsvetan Serchov, head of the Department of Stereotactic and Functional Neurosurgery at the Department of Neurosurgery at the Freiburg University Medical Centre.

A therapeutic approach from the 1980s might gain new importance

The researchers used a process that has been known since the late 1980s but has so far hardly been used for therapeutic purposes. They linked a tiny protein from the HI virus with the protein Homer1a, which is important for depression therapy. Due to its physical and chemical properties, the HIV protein can easily penetrate the cell membrane. It transports the therapeutically effective Homer1a protein through the blood-brain barrier and into the cell. 

In the experimental setting, after the double molecule had been introduced into the blood of the mice, it only took about an hour for the antidepressant effect to set in. In recent years, the Freiburg research team had identified the protein Homer1a as an important cellular mediator in the treatment of depression. "In earlier studies, we were able to show that not only drugs but also the antidepressant effect of sleep deprivation lead to the activation of Homer proteins," said Dr. Serchov.

Use as a nasal spray could be possible

The current study, which was carried out in close cooperation with the Department of Psychiatry and Psychotherapy at the Freiburg University Medical Centre, also showed how Homer proteins exert their antidepressant effect. They activate surface proteins which enable the cell to react more strongly to stimuli. This makes adaptation and learning easier. If the proteins Homer and AMPA receptors are produced less strongly, as in the brains of people with severe depression, these processes become more difficult for those affected. 

"The therapeutic approach has been very successful in the laboratory and in animal models. Further studies must now follow on possible side effects, the metabolism of the active substance and the specific psychiatric use," said Dr. Serchov. "In the long term, it is conceivable that the drug will also be used as a nasal spray. This would bring it directly to the correct region of the brain, the prefrontal cortex”, he added.

Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid Antidepressant Effects via AMPA Receptor Activation
Amrei Holz, Felix Mülsch, Martin K. Schwarz, Michael Hollmann, Mate D. Döbrössy, Volker A. Coenen, Marlene Bartos, Claus Normann, Knut Biber, Dietrich van Calker, Tsvetan Serchov
DOI: 10,1016/y.neuron.2019.07.011