Systematic Review on the Involvement of the Kynurenine Pathway in Stroke: Pre-clinical and Clinical Evidence

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Systematic Review on the Involvement of the Kynurenine Pathway in Stroke: Pre-clinical and Clinical Evidence

Gabriela D. Colpo^1*, Venugopal R. Venna², Louise D. McCullough² and Antonio L. Teixeira^1*

• ¹Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, United States
• ²BRAINS Lab, Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX, United States

Background: Stroke is the second leading cause of death after ischemic heart disease and the third leading cause of disability-adjusted life-years lost worldwide. There is a great need for developing more effective strategies to treat stroke and its resulting impairments. Among several neuroprotective strategies tested so far, the kynurenine pathway (KP) seems to be promising, but the evidence is still sparse.

Methods: Here, we performed a systematic review of preclinical and clinical studies evaluating the involvement of KP in stroke. We searched for the keywords: (“kynurenine” or “kynurenic acid” or “quinolinic acid”) AND (“ischemia” or “stroke” or “occlusion) in the electronic databases PubMed, Scopus, and Embase. A total of 1,130 papers was initially retrieved.

Results: After careful screening, forty-five studies were included in this systematic review, being 39 pre-clinical and six clinical studies. Despite different experimental models of cerebral ischemia, the results are concordant in implicating the KP in the pathophysiology of stroke. Preclinical evidence also suggests that treatment with kynurenine and KMO inhibitors decrease infarct size and improve behavioral and cognitive outcomes. Few studies have investigated the KP in human stroke, and results are consistent with the experimental findings that the KP is activated after stroke.

Conclusion: Well-designed preclinical studies addressing the expression of KP enzymes and metabolites in specific cell types and their potential effects at cellular levels alongside more clinical studies are warranted to confirm the translational potential of this pathway as a pharmacological target for stroke and related complications.

Introduction

Stroke is clinically defined by the sudden onset of focal neurological symptoms (motor, sensory, cognitive) due to ischemia or hemorrhage in the brain. It is the second leading cause of death after ischemic heart disease and the third leading cause of disability-adjusted life-years lost worldwide (1). In the last two decades, there has been significant advance in the acute management of stroke, including the establishment of dedicated stroke inpatient units and the use of thrombolysis for eligible patients with ischemic stroke. Despite this progress, stroke-related deaths and morbidity remain a major health problem with personal and societal implications.

To address the great need of advancing stroke management, several mechanisms implicated in the pathophysiology of stroke, such as mitochondria dysfunction, glutamate-induced excitotoxicity, neuroinflammation, oxidative stress, among others, have been investigated as therapeutic targets. Among putative candidates, the kynurenine pathway (KP) received attention in the 1990's with a renewed interest recently on the wave of inflammatory-centric perspective of central nervous system diseases, including stroke (2).

The KP is the major route of tryptophan (TRP) catabolism in mammals. TRP is an essential amino acid used in the biosynthesis of proteins, being also a precursor of several bioactive molecules, such as serotonin and melatonin. Around 90% of TRP is metabolized by tryptophan 2,3-dioxygenase (TDO) into kynurenine (KYN) in the liver, with a much lower contribution of extra-hepatic KP on TRP degradation (5–10%) (3). TDO is liver specific, but two TDO variants been identified in mouse brain structures during development (4).

In extrahepatic tissues, especially cells of the immune and central nervous systems, the KP is initiated by the degradation of TRP by indoleamine 2, 3-dioxygenase 1 (IDO), the rate limiting enzyme of the pathway. This enzyme is potently upregulated by pro-inflammatory stimuli (2). After this step, the KP branches into two major pathways–one implicated in neuroprotection, the other in neurotoxicity–that are segregated across cell types (Figure 1). Under physiological conditions, the neuroprotective branch is more active as most of kynurenine in the brain is metabolized into kynurenic acid, a NMDA and α7-nicotinic acetylcholine receptor antagonist, through the action of kynurenine aminotransferases (KATs) expressed mainly in astrocytes (5). Under inflammatory conditions, the metabolism is shifted through kynurenine-3-monooxygenase (KMO) to produce 3-hydroxykynurenine and other toxic metabolites, including quinolinic acid, a NMDA receptor agonist and an oxidative stressor (3, 6). KMO is primarily expressed in microglia, the resident immune cells in the brain, and is also expressed at high levels in peripheral immune cells such as monocytes/macrophages (7).