Funding tool: Basic research projects
Project-ID: LS10-032
Project start: 01. August 2011
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 269.999,00

Brief summary:

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system, which cause is not cleared yet.
The knowledge about brain tryptophan metabolism along the kynurenine pathway gained more attention for its involvement in neurodegenerative and recently also in neuroinflammatory diseases. There are evidences suggesting that the kynurenine pathway is very likely to play an important role in the regulation of autoimmune diseases.
The immune modulatory treatment with ?-interferon involves induction of IDO and formation of neuroactive compounds with potential impact on MS symptomatic. A particular role relates to quinolinic acid and 3-OH-kynurenine with neurotoxic and kynurenic acid with neuroprotective properties. Kynurenic acid is synthesized from L-kynurenine in glia and kynurenine aminotransferases (KATs) are involved. Our investigations show a marked decrease of KATs activities in post mortem brain and the spinal cord of chronic MS patients (post to mortem material), indicating a deficit of neuroprotection in MS brains. In acute onset (relapse) of the disease we found an enhancement of KYNA in cerebrospinal fluid (CSF) and this might be due to glia activation. We found that human CSF has an ability (factor) to block KAT activity and this factor we postulated as "glia depressing factor" (GDF) with possible regulatory capacity. Our first results showed a reduction of GDF in CSF of MS patients and revealed data are in line with glia activation, plaque formation and increased kynurenic acid levels, respectively.
The aim of the project is the investigation of tryptophan metabolism along the kynurenine pathway i.e. the measurement of L-tryptophan, L-kynurenine, kynurenic acid, anthranilic acid, 3-OH-kynurenine and 3-OH-anthranilic acid levels in serum and CSF in 800 patients with diagnoses of MS, clinically isolated syndrome, acute disseminated encephalomyelitis, neuroborreliosis, acute inflammatory demyelinating polyneuropathy, amyotrophic lateral sclerosis, diabetic polyneuropathy and control subjects in a retrospective study to characterize the profile of tryptophan metabolites alterations. Also for the first time the GDF will be searched to find specific characteristics of investigated diseases. Ratio obtained from two GDF activities yield a marker which we have suggested as a diagnostic marker of MS. The selectivity and the specificity of the developed biomarker (Ratio) for MS will be proved by 800 CSF samples. Data obtained from this study should provide for the first time significant incites for new diagnostic and treatment strategy for MS and other diseases, furthermore indication for advantage of isolation, identification and genetic reproduction of GDF.

Keywords:
Multiple Sclerose; Tryptophan; Kynurensäure; Kynureninabbauweg; Biomarker; Glia Depresing Factor; Kynureninaminotransferase; neuroinflammatorische Erkrankungen; neurodegenerative Erkrankungen;