The Kynurenine Pathway in the Acute and Chronic Phases of Cerebral Ischemia

Abstract

Kynurenines are a wide range of catabolites which derive from tryptophan through the “Kynurenine Pathway” (KP). In addition to its peripheral role, increasing evidence shows a role of the KP in the central nervous system (CNS), mediating both physiological and pathological functions. Indeed, an imbalance in this route has been associated with several neurodegenerative disorders such as Alzheimer’s and Huntington’s diseases. Altered KP catabolism has also been described during both acute and chronic phases of stroke; however the contribution of the KP to the pathophysiology of acute ischemic damage and of post-stroke disorders during the chronic phase including depression and vascular dementia, and the exact mechanisms implicated in the regulation of the KP after stroke are not well established yet. A better understanding of the regulation and activity of the KP after stroke could provide new pharmacological tools in both acute and chronic phases of stroke. In this review, we will make an overview of CNS modulation by the KP. We will detail the KP contribution in the ischemic damage, how the unbalance of the KP might trigger an alteration of the cognitive function after stroke as well as potential targets for the development of new drugs.

Plasma metabolomics supports the use of long-duration cardiac arrest rodent model to study human disease by demonstrating similar metabolic alterations

“…However, these striking similarities were observed within the first hour in humans and first half hour in rats after resuscitation, indicating that unlike previous studies, alterations in the tryptophan and kynurenine pathway metabolites occur almost immediately postresuscitation. A higher kynurenine to tryptophan ratio observed in both preclinical and clinical studies of brain injury [48][49][50][51] and cardiovascular disease 52 indicated worse clinical outcomes implicating oxidative and inflammatory stress. Controversially, ischemic damage induced by CA may increase kynurenic acid, which may serve a protective role, as kynurenic acid has neuroprotective effects, while 3-hydroxyanthranilic acid and downstream quinolinic acid have a proclivity for neurotoxicity 50,53 .…”

High neopterin and IP-10 levels in cerebrospinal fluid are associated with neurotoxic tryptophan metabolites in acute central nervous system infections

“…Neurologic dysfunction is common in patients with encephalitis and bacterial meningitis, and dysregulation of the KP has been shown in syndromes and disorders with certain overlap in symptoms [ 21 , 30 , 32 , 56 , 57 ]. Herein, we compared these metabolites in patients with a stringent definition of etiology; encephalitis, confirmed viral meningitis, and bacterial meningitis.…”

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…In the acute ischemic phase, the tissue is affected by a sequence of molecular and cellular events due to a decrease in the CBF. This sequence of events is called the ischemic pathway, which begins with energy depletion and glutamate excitotoxicity, and ends in cell death (Lai et al, 2014;Cuartero et al, 2016; Figure 1). According to the changes in membrane potential, the most vulnerable cells to 30-min OGD are neurons, followed by astrocytes, while NG2 glia showed no significant pathological alterations (Du et al, 2018).…”