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Inflammatory reactions determine the quality of neuroregeneration

Prof. Dr. Hermann J. Schlüsener (Photo: private)

Prof. Dr. Hermann J. Schlüsener (Photo: private)

Regenerative therapies in the central nervous system (CNS) are a particular challenge because traumatic primary injuries lead to secondary damage that also needs to be treated.

Damage to the central nervous system (CNS), i.e. in the brain and spinal cord, often have serious consequences. One example is traumatic brain injuries following a fall and impact to the head. "The primary injuries cannot usually be pharmacologically treated," said Prof. Dr. Hermann Schlüsener from the Institute of Brain Research at the University of Tübingen. "However, after a trauma, severe secondary damage, for example oedemas, usually develops within just a few days. The swelling might lead to a massive pressure in the brain. In addition, the injury leads to apoptosis, i.e. programmed cell death of neurones, and large-scale tissue degeneration," said the scientist.

Secondary damage is often a major problem for people with spinal marrow injuries. Scar tissue forms, which often impedes the growth of neurones. In addition, oedemas and massive inflammatory reactions might occur around the site of injury. These phenomena prevent both natural neuroregeneration, which does actually occur to a certain extent, as well as the therapeutical regeneration of the damaged area. Schlüsener and his group of researchers are working on ways to prevent such complications. A major aspect of their research is the modulation of inflammatory reactions.

Selective addressing of active substances and immune system cells

Schlüsener touches on two possibilities for pharmacologically addressing the inflammation process. As part of a BioRegio STERN BioProfile project, Schlüsener and Tübingen-based Synovo GmbH are working on introducing an anti-inflammatory agent into the body that will act solely on the affected blood vessels. Such selective targeting is pharmacologically highly sophisticated. Schlüsener and his partners are developing DNA aptamers (single-strand oligonucleotides), which are then coupled to the active agent. These aptamers, which have a three-dimensional structure similar to the complex structure of proteins, are responsible for the required selective targeting.

"In vitro, targeting using aptamers works well. Our next step will be to investigate the pharmacodynamics in the animal model," explains Schlüsener. The scientists are examining different parameters such as size and stability of the complexes in order to create an optimal connection. For the pharmaceutical industry, aptamers have the enormous advantage of being able to be precisely reproduced using automated methods. This makes them particularly interesting for therapeutic approaches, and also for use in regenerative medicine.

Schlüsener’s research group is also working with Synovo GmbH in a second BioProfile project, in which the researchers are looking for a way to specifically control the cells of the immune system. "We are trying to find out whether we are able to specifically control particular macrophages in order to induce regeneration and combat inflammatory reactions," said Schlüsener, summarising the goal of the project.

Side effects associated with damage and therapy are important for research

In parallel to these research activities, Schlüsener is also examining pain states in the spinal marrow that might be associated with lesions or regenerative processes. "It is not sufficient to induce the growth of nerves as part of a regenerative therapy by switching off growth inhibitors and inducing growth factors. Regeneration is often associated with pain that must also be treated," explained Schlüsener, who is considering different ways for treating such pain pharmacologically.

Simplified representation of a chronic spinal marrow lesion with secondary damage and potential intervention strategies for improving the remaining neurological function (Figure: UKT/Institute of Brain Research)

Simplified representation of a chronic spinal marrow lesion with secondary damage and potential intervention strategies for improving the remaining neurological function (Figure: UKT/Institute of Brain Research)

Another approach focuses on stem cells that might be used in therapy, at least as a backup measure. The stem cells could possibly replace dead neurones, thus potentially stimulating the growth of new nerve fibres. "In the spinal marrow, we find cells with a stem-cell like ability to divide. We are examining different substances to see whether they are able to retain these cells in the proliferation stage," said Schlüsener. Synovo provides the substances required for these tests while Schlüsener’s group focuses on the cells, examining the mechanisms of proliferation and the possibilities of interfering with this process.

Valuable support through Chinese partners

There is no doubt that the diversity of the projects involves a lot of work, experiments and people in order to pursue all approaches with the same level of commitment. Since Schlüsener has neither the financial nor personnel resources for all these projects, he is working in cooperation with Chinese universities. "The majority of experiments are done in Shanghai and Wuhan. That’s my definition of globalisation," said Schlüsener.

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Immunohistological staining (brown) of P2X4 receptors (P2X4R, an ATP sensor) in the rat brain to represent activated monocytes that are migrating into the trauma site (48 hours after trauma): (A) the area of secondary damage comprises the area where the primary injury occurred and there are numerous activated microglia/macrophages that express P2X4R. (B) True tissue structures are hardly discernible in the necrotic areas. (C) In areas further away from the injury the tissue is hardly affected.

Schlüsener has developed joint study programmes and projects for training the teams in China. That’s his contribution to quality assurance. "For a fraction of the cost, high-quality work meeting international standards is carried out by our Chinese partners."

leh - 03.03.2007
© BIOPRO Baden-Württemberg GmbH, first published at www.bio-pro.de<, the Biotech/Life Sciences Portal of the State of Baden-Württemberg. All rights reserved.

Further information:

University Hospital of Tübingen
Institute of Brain Research

Prof. Dr. Hermann J. Schlüsener
Calwerstraße 3
72076 Tübingen

Phone: +49 (0)7071 29-84881
Fax: +49 (0)7071 29-5456
schluesener [at] uni-tuebingen [dot] de