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Halina Baran

Karl Landsteiner Research Institute for Neurochemistry and Neuropharmacology, Austria

Title: Lowering of kynurenic acid formation – anti-dementia drugs



Kynurenic acid (KYNA) is an endogenous metabolite of the kynurenine pathway of tryptophan degradation and is an
antagonist of the glutamate ionotropic excitatory amino acid and of the nicotine cholinergic receptors and its involvement
in memory impairment has been suggested. The therapeutic effect of Cerebrolysin treatment of dementia and of brain injury
has been proposed because of neurotrophic properties of this compound. Since an increased kynurenine metabolism has
been shown in several brain pathologies including dementia we investigated the biochemical properties of Cerebrolysin with
respect to KYNA formation in an in vitro study. The activities of the KYNA synthesising enzymes kynurenine aminotransferase
I, II and III (KAT I, KAT II, KAT III) in rat liver, and rat and human brain homogenates were analysed in the presence of
Cerebrolysin. Data revealed demonstrate the ability of Cerebrolysin to lower KYNA formation in homogenates. We suggest
that the anti-dementia effect of Cerebrolysin observed in Alzheimer patients could be due to Cerebrolysin induced reduction
of KYNA levels, thus enhancing the cholinergic and glutamatergic neurotransmissions. D-Cycloserine, anti- mycobacterial
drug, known as a partial agonist at the glycine modulatory site of the glutamatergic NMDA receptor, exerts anticonvulsive
activities and improves cognitive function. We evaluated the action of D-cycloserine with respect to the biosynthetic machinery
of KYNA synthesis. Interestingly, we found that D-cycloserine blockes significantly KATs activities in rat liver and brain
homogenates and in the frontal cortex homogenate of human post mortem tissue, as well. These results allowed us to propose
that lowering of KYNA content likely due to D- cycloserine inhibition of KATs activities might be involved in the postulated
mechanism for D- cycloserine to act as a partial agonist at the glycine site of the NMDA receptor. It is reasonable to believe
that this mechanism(s) is in part responsible for the improvement of symptoms like dementia, cognition and/or delusion
in schizophrenia patients, Alzheimer’s, HIV-1 infected patients or Parkinson’s patients. Finally we evaluated the action of
Jerusalem balsam with respect to the biosynthetic machinery of KYNA synthesis. Jerusalem balsam is widely used because of
good reputation as a natural remedy. It is a mixture of certain plants, which supposes to have antibacterial and anti-oxidative
properties. Jerusalem balsam is used to improve liver and lung diseases, as for example bronchopneumonia. Interestingly,
we found that Jerusalem balsam blocks significantly KATs activities, too. Lowering of KYNA synthesis by Jerusalem balsam
represents notable biochemical effect since it might influence KYNA levels. Therefore increased KYNA levels observed in
stroke patient, in patient with respiration and cardiovascular problem, in neuropsychiatric disorders, in patient infected with
HIV-1 and patients with bronchopneumonia could be treating by Jerusalem balsam. We speculate the possible therapeutic
application and advantage of the remedy Jerusalem balsam, i.e. mixture of plants and discuss comparing to effect of antidementia
drugs D-cycloserine and Cerebrolysine.