Scripties UMCG - Rijksuniversiteit Groningen
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The regulation of the kynurenine pathway with an impaired blood-brain barrier

(2018) Zielstra, R.

Background: The kynurenine pathway (KP) has been studied in a wide variety of diseases. Tryptophan(TRP) is degraded along the KP into kynurenine(KYN) and subsequently into kynurenic acid(KYNA) or quinolinic acid(QUIN). Most interesting is the disbalance between the neurotoxic QUIN and neuroprotective KYNA. Since QUIN can destroy astrocytes, this could lead to reduced production of KYNA by these cells, creating a disbalance between QUIN and KYNA. Previous studies focussed on the change in KP metabolites in neurological and psychiatric diseases. However, the physiological regulation of the KP and the crossing of QUIN and KYNA remain unclear for an impaired BBB. Therefore, the current study researched the physiological regulation of the KP and the crossing of QUIN and KYNA across an impaired BBB. Method: The Anaesthetic Biobank of Cerebrospinal Fluid(CSF) delivered samples of blood and CSF. The BBB function was calculated with the Q-albumin(Q-alb) and two groups, intact and impaired BBB, were formed based on the age-dependent reference values. TRP, KYN, QUIN, and KYNA were compared between the groups for blood and CSF, as were the KYN-TRP and QUIN-KYNA ratio for both groups. Lastly, a correlation between the KP-metabolites ratios and Q-alb was performed. Results: 89 Patients in the intact BBB group and 30 patients in the impaired BBB group were analysed. Both KYN-TRP and QUIN-KYNA ratio in CSF were higher with an impaired BBB. The KYN and QUIN ratio (CSF/blood) were also higher for the impaired BBB group. There were multiple significant correlations between Q-alb and the following ratios: KYN-TRP (blood), KYN-TRP (CSF), KYN (CSF/blood), QUIN (CSF/blood), KYNA (CSF/blood) and QUIN-KYNA (CSF). Conclusion: the KP in CSF is up-regulated when the BBB is impaired. Our results supports previous literature studying the KP in diseases that can potentially affect the BBB. Since the QUIN-KYNA ratio in CSF is higher with the impaired BBB and the QUIN-KYNA ratio in blood was not different, it is likely that QUIN and KYNA do not cross the impaired BBB. Future research could distinguish better between local production and diffusion of KYNA and QUIN across the impaired BBB.

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