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More targeted treatment of the brain network

“Casting out the demons with the ruler of the demons” – is what the majority of neuroactive drugs still do. A group under the leadership of Dr. Ralf Meyer at the University Medical Centre in Freiburg is investigating why substances used to treat epilepsy or depression have a negative effect on many patients. Their research shows that the drugs interact with the hormonal system, resulting in undesired side effects. Meyer and his team of researchers hope that their systemic research will be able to prevent such interactions from occurring.

Libido disorders, menstruation problems, perception deficiencies are all potential undesired side effects of standard anti-epileptic drugs. Why do such side effects occur? Dr. Ralf Meyer of the Department of Neuropathology at the Neurocentre at the Freiburg University Medical Centre asked himself this question after reading an American report identifying the correlation between anti-epileptic drugs and the aforementioned side effects. These side effects were particularly shown to occur in patients who had taken cytochrome P450-inducing drugs. Cytochrome P450 is a family of enzymes that metabolises steroid hormones such as testosterone or oestrogen as well as toxic substances in the liver. “Nowadays, we are able to achieve a detailed understanding of the character changes experienced by patients taking certain neuroactive drugs,” said Mayer who, together with this team of researchers, has elucidated the molecular mechanisms underlying such changes.

A molecular network and the psyche

The key in terms of these side effects is cytochrome P450, which has been at the centre of Meyer’s investigations ever since he did his doctorate. Drugs used to treat epilepsy and depression as well as neurodegenerative diseases such as dementia, lead to an increase in the quantity of cytochrome P450 in certain brain cells. The affected cells are mainly located in the hippocampus, the hypothalamus, the cerebellum or in the amygdala. These are all brain areas involved in the control of emotions, libido, perception and memory. Cell culture and animal experiments clearly show the consequences of cytochrome P450 induction: the concentration of testosterone in the brain decreases whilst that of oestrogen increases. Metabolic studies show that the number of testosterone degradation products increases in the brain and in the blood, which means that larger amounts of testosterone are degraded. Another consequence observed by the Freiburg researchers is the elevated number of testosterone receptors in the brain cells, which normally serve to translate a testosterone signal into the cells’ interior. This seems to be a compensatory reaction of the neurones in their attempt to increase the hormonal effect as a result of the sudden lack of hormone.

The mouse brain under the fluorescence microscope after being treated with cytochrome P450-inducing anti-epileptic drugs (here: phenytoin), the number of androgen receptors (green) and P450 (red) in the neurones of three brain regions increases. The blue colour shows the cells (staining of the nucleus with the neuronal nuclear protein NeuN). The white spots in the right column show where the number of androgen receptors and cytochrome P450 increases.
The mouse brain under the fluorescence microscope after being treated with cytochrome P450-inducing anti-epileptic drugs (here: phenytoin), the number of androgen receptors (green) and P450 (red) in the neurones of three brain regions increases. The blue colour shows the cells (staining of the nucleus with the neuronal nuclear protein NeuN). The white spots in the right column show where the number of androgen receptors and cytochrome P450 increases. © Dr. Ralf P. Meyer
Following the treatment of a patient with cytochrome P450-inducing anti-epileptic drugs (in this case, carbamazepin), the quantity of androgen receptors (green) considerably increases. Top: control patient with no neurological symptoms; below: epileptic patient treated with carbamezepin. The photo shows hippocampal neurones. © Dr. Ralf P. Meyer

"The increase in the number of receptors shows that the consumption of drugs leads to a change in the balance of the signalling pathways of the brain hormones," said Meyer. "Hormones such as testosterone or oestrogen regulate many mental processes; these are unbalanced in the patient groups mentioned above." How can these disorders be prevented? Is it possible to specifically regulate this imbalance with specific interventions? Experiments involving small RNA molecules (siRNA) that block the production of cytochrome P450 show that this is indeed possible. The number of receptors decreases once lower P450 levels are reached. However, these experiments only represent initial evidence obtained from cell culture and mouse experiments. A drug that would be able to reduce P450 in the cell is still a long way off. At the moment, Meyer and his team are more interested in a completely different approach: "All neuroactive drugs will at some stage be broken down in the brain," said Meyer. "This leads to toxic intermediary products that can even induce cancer." Therefore, a remote control to prevent drugs from even entering the brain could be helpful. There is a particular tissue that seems to be promising - the brain-blood barrier.

Looking for correlations

"The blood-brain barrier separates the circulating blood from the brain tissue," said Meyer. Protein channels in the membranes of the cells in the blood-brain barrier control the passage of substances into the brain. Sensors at this separation point can also register drugs that are transported with the blood into the brain and regulate their import into the brain tissue. However, these sensors also communicate with cytochrome P450. "It appears that neuroactive drugs already exert their effect on cytochrome P450 and the hormone systems in the brain at this point," said Meyer. "Therefore, we are planning to investigate the molecular relationships between the blood-brain barrier and the neurones behind it," said Meyer explaining that the researchers will test knock-out mice lacking sensors for foreign substances in their blood-brain barrier cells. How do the cytochrome P450 system and the hormonal networks react in such mice?

"We hope that future developments will lead to drugs that only exert their action before they cross the blood-brain barrier, from where they will control the signalling networks of the brain without generating the side effects that they do at the moment," said Meyer. The metabolism in the brain is a very complex process, and Meyer is convinced that holistic systems biology approaches are needed to gain in-depth insights. "Without knowledge about the relationships between all molecular players involved, we will be unable to come up with an intelligent drug design," said Meyer.

 

Further information:
PD Dr. Ralf P. Meyer
Medical Faculty of the University of Freiburg
Breisacherstraße 64
79106 Freiburg
Tel.: +49-(0)761/450-2956
E-mail: ralf.meyer(at)uniklinik-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/more-targeted-treatment-of-the-brain-network