Kynurenine and its metabolites in Alzheimer's disease patients
Section snippets
INTRODUCTION
The kynurenine pathway is a major route of tryptophan (TRP) metabolism. Two metabolites of TRP: kynurenic acid (KYNA) and quinolinic acid (QUIN) are able to interact with N-methyl-D-aspartate receptor (NMDA). KYNA is endogenous NMDA antagonist with neuroprotective activity while QUIN being its agonist is neurotoxic [1, 2, 3]. Over-stimulation of NMDA could account for neuronal death by excitotoxicity [4, 5]. QUIN leads to neuronal dysfunction also by other mechanisms [6, 7, 8]. It can provoke
Subjects
Thirty four AD patients (10 men, 24 women, mean age 78.82±5.66 years) and 18 age- and sex-matched controls (CNTs) (5 men, 13 women, mean age 76.17±7.30 years) were enrolled in the study (Tab. 1). Exclusion criteria were: infectious disease defined by high C-reactive protein level, kidney and liver insufficiency, chronic corticosteroids intake and cerebral ischaemic stroke in the past.
The DSM-IV (Diagnostic and Statistical Manual of Mental Disorders of American Psychiatric Association) criteria
RESULTS
Clinical and laboratory parameters in Tab. 1 of AD patients did not differ from control group (all p>0.05).
Tab. 2 shows serum concentrations of TRP, KYN, 3-HK, AA, KYNA and QUIN and their corresponding quotients: KYN/TRP, AA/KYN, KYNA/KYN, 3-HK/KYN, QUIN/3-HK in AD patients and in a control group. TRP concentrations were lower (p<0.001), and KYN levels were non-significantly increased in AD patients compared to CNTs. KYNA concentrations were significantly (p<0.002) decreased in the AD plasma.
DISCUSSION
At present, the AD diagnosis must be confirmed by postmortem examination of the brain. Currently, the ante-mortem diagnosis is still based on the integration of multiple data (clinical, paraclinical and biological analyses) because no unique marker exists for such disease. The kynurenine pathway (KP) is a central route in the TRP metabolism in most mammalian tissues, including brain [4, 5]. It has been showed that level of KYN in the CSF remain unchanged in AD [10], while the KYNA level is
CONCLUSIONS
Increased TRP degradation and simultaneous altered kynurenines levels were found in plasma of AD patients. It proves activation of peripheral kynurenine pathway in this type of dementia. The alterations of two main KYN metabolites: KYNA and QUIN seem to be associated with the impairment of the cognitive function in AD patients. This appears to offer novel therapeutic opportunities, with the development of new compounds as a promising perspective for brain neuroprotection.
ACKNOWLEDGEMENTS
This work was supported by a grant (No. 3-11667) from the Medical University in Bialystok, Poland
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