Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection

Abstract

There is good evidence that the kynurenine pathway (KP) and one of its products, quinolinic acid (QUIN), play a role in the pathogenesis of neurological diseases, in particular AIDS dementia complex. Although QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the role of astrocytes in QUIN production is controversial. Using cytokine-stimulated cultures of human astrocytes, we assayed key enzymes and products of the KP. We found that human astrocytes lack kynurenine hydroxylase so that large amounts of kynurenine and the QUIN antagonist kynurenic acid were produced. However, the amounts of QUIN that were synthesized were subsequently completely degraded. We then showed that kynurenine in concentrations comparable with those produced by astrocytes led to signi®cant production of QUIN by macrophages. These results suggest that astrocytes alone are neuroprotective by minimizing QUIN production and maximizing synthesis of kynurenic acid. However, it is likely that, in the presence of macrophages and/or microglia, astrocytes become indirectly neurotoxic by the production of large concentrations of kynurenine that can be secondarily metabolized by neighbouring or in®ltrating monocytic cells to form the neurotoxin QUIN.

In Vivo Uptake and Metabolism of α-[11C]Methyl-l-Tryptophan in Human Brain Tumors

“…This mechanism would be consistent with previous studies showing high quinolinic acid content in epileptogenic tubers, showing increased AMT uptake on PET (Chugani et al, 1998b;Chugani and Muzik, 2000). While conversion of tryptophan to N-formylkynurenine by IDO occurs (and can be induced by gamma interferon) in glial cells (Heyes et al, 1997;Grant and Kapoor, 2003), synthesis of quinolinic acid requires the copresence of monocytic cells (Saito et al, 1993;Heyes et al, 1997;Guillemin et al, 2001); thus, there might not be a direct correlation between tryptophan metabolic rates, quinolinic acid levels, and seizure activity in brain tumors. In addition, other factors, such as tumor location, patient's age, and genetic factors, might also have an influence on whether clinical seizures occur (Bartolomei et al, 1997;Lote et al, 1998).…”

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

“…Although several of these enzymes may participate in cerebral KYNA biosynthesis under physiological and pathological conditions, it appears that the pool of KYNA that can be most readily mobilized in the brain is largely provided by KAT-II (Amori et al, 2009). This enzyme is almost exclusively localized in astrocytes (Guidetti et al, 2007b;Guillemin et al, 2001), which rapidly liberate newly synthesized KYNA into the extracellular milieu (Curatolo et al, 1996;Guillemin et al, 2000). Although the precise mechanism controlling the release of KYNA has not been elucidated, this insight led to the development of specific KAT-II inhibitors, which are designed to target astrocytes and reduce extracellular KYNA concentrations.…”

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

“…However, unlike tryptophan, which serves as a substrate for serotonin biosynthesis in neurons, brain KYN is preferentially metabolized in astrocytes and microglial cells. Accordingly, these cells serve as the primary source of QUIN and KYNA in the brain (Guillemin et al, 2001;Schwarcz and Pellicciari, 2002). To date, most hypotheses involving the kynurenine pathway have emphasized the potential pathophysiological significance of elevations in brain QUIN, a potent excitotoxin and NMDA receptor agonist (Stone, 2001).…”