Age-related increase of kynurenic acid in human cerebrospinal fluid - IgG and beta2-microglobulin changes.
Kynurenic acid (KYNA) is an endogenous metabolite in the kynurenine pathway of tryptophan degradation and is an antagonist at the glycine site of the N-methyl-D-aspartate as well as at the alpha 7 nicotinic cholinergic receptors. In the brain tissue KYNA is synthesised from L-kynurenine by kynurenine aminotransferases (KAT) I and II. A host of immune mediators influence tryptophan degradation. In the present study, the levels of KYNA in cerebrospinal fluid (CSF) and serum in a group of human subjects aged between 25 and 74 years were determined by using a high performance liquid chromatography method. In CSF and serum KAT I and II activities were investigated by radioenzymatic assay, and the levels of beta(2)-microglobulin, a marker for cellular immune activation, were determined by ELISA. The correlations between neurochemical and biological parameters were evaluated. Two subject groups with significantly different ages, i.e. <50 years and >50 years, p < 0.001, showed statistically significantly different CSF KYNA levels, i.e. 2.84 +/- 0.16 fmol/microl vs. 4.09 +/- 0.14 fmol/microl, p < 0.001, respectively; but this difference was not seen in serum samples. Interestingly, KYNA is synthesised in CSF principally by KAT I and not KAT II, however no relationship was found between enzyme activity and ageing. A positive relationship between CSF KYNA levels and age of subjects indicates a 95% probability of elevated CSF KYNA with ageing (R = 0.6639, p = 0.0001). KYNA levels significantly correlated with IgG and beta(2)-microglobulin levels (R = 0.5244, p = 0.0049; R = 0.4253, p = 0.043, respectively). No correlation was found between other biological parameters in CSF or serum. In summary, a positive relationship between the CSF KYNA level and ageing was found, and the data would suggest age-dependent increase of kynurenine metabolism in the CNS. An enhancement of CSF IgG and beta(2)-microglobulin levels would suggest an activation of the immune system during ageing. Increased KYNA metabolism may be involved in the hypofunction of the glutamatergic and/or nicotinic cholinergic neurotransmission in the ageing CNS.
Kepplinger
Berthold
B
Department of Neurology, Klinikum Mostviertel Amstetten, General Hospital, Amstetten, Austria.
Baran
Halina
H
Kainz
Astrid
A
Ferraz-Leite
Heber
H
Newcombe
Jea
J
Kalina
Pavol
P
D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D000704:Analysis of Variance; D001923:Brain Chemistry / Q000502:physiology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000134:cerebrospinal fluid*; D007736:Kynurenic Acid / Q000097:blood / Q000134:cerebrospinal fluid*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011863:Radioimmunoassay / Q000379:methods; D000637:Transaminases / Q000097:blood / Q000134:cerebrospinal fluid; D001613:beta 2-Microglobulin / Q000097:blood / Q000134:cerebrospinal fluid*
D007074:Immunoglobulin G; D001613:beta 2-Microglobulin; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid