Age-Related Increase of Kynurenic Acid in Human Cerebrospinal Fluid – IgG and β₂-Microglobulin Changes

Abstract

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 β₂-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/µl vs. 4.09 ± 0.14 fmol/µl, 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 β₂-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 β₂-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.

Normal Pressure Hydrocephalus, Dementia and Kynurenic Acid

“…Levels of kynurenic acid in CSF and serum of control subjects correlated well with data previously published [8]. The age 49 years of patient with normal pressure hydrocephalus corresponded with the age of used control subjects (between 18-50 years).…”

“…An enhancement of kynurenic acid in CSF of patients with hydrocephalus represent significant finding since there are many neurological disorders demonstrating correlation between increased kynurenic acid in CNS and occurrences of dementia and/or cognition impairment, i.e., in Alzheimer, HIV-1 infection/AIDS, Schizophrenia even aging [3][4][5][6][7][8]. Whereas an enhancement of kynurenic acid levels in the serum can increase the cardiovascular disease risk factor [14].…”

“…Measurement of kynurenic acid: Measurement of kynurenic acid was performed as described by Kepplinger et al [8]. Briefly, CSF and serum sample was mixed with 0.2 M HCl (vol/vol), proteins were precipitated by adding 50% TCA, and sample centrifuged (20 min, 14,000 rpm).…”

“…Accumulated data demonstrate enhanced kynurenic acid levels in the CNS in various neuropsychiatric disorders with dementia and in the aging process [6][7][8].…”

Jerusalem Balsam Lowers Kynurenic Acid Formation: An In Vitro Study

“…Kynurenic Acid (KYNA), an intermediate metabolite of L-kynurenine, is a competitive antagonist of ionotropic Excitatory Amino Acid (EAA) receptors and a non-competitive antagonist of 7 alpha nicotine cholinergic receptors and its involvement in memory deficit and cognition impairment has been suggested [3][4][5]. KYNA is altered significantly in various neuropsychiatric and immunologic disorders [6][7][8] and also in aging process [9]. Alterations of L-TRP metabolite levels in the blood found immediately after strokes indicate a significant activation of metabolism along the kynurenine pathway and increase the cardiovascular risk factor, as well [10][11][12].…”