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

Abstract

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.

Tryptophan Metabolism, Inflammation, and Oxidative Stress in Patients with Neurovascular Disease

“…TRP levels in neurovascular patients were significantly lower as compared with controls, with significantly lower levels of TRP in AIS patients compared to patients with SCAS. The result is in accordance with systematic Colpo's review evaluating the involvement of KP in stroke [24] and with Wang's review about dysregulation of KP in inflammation [27]. Accordigly, neurovascular patients had both enhanced inflammation marker NEO (AIS patients significantly) and KTR ((SCAS patients significantly) as compared with controls.…”

“…However, KYN concentrations in neurovascular patients were not significantly different compared to controls, nevertheless KYN concentrations in SCAS patients were significantly higher compared to AIS patients. The results do not correspond neither to Colpo's review for stroke [24] nor to Pawlak's results about KYN and QA linked to carotid atherosclerosis in patients with end-stage renal disease [43]. However, Ormstad et al also did not found significant differences of both KYN levels and KTR values in patients with AIS [44].…”

“…It was reported that abnormal KP is involved in neurological disorders [22], cancer [8], cardiovascular diseases (CVD) [23], and in stroke [24]. One of the risk factors for stroke is carotid artery stenosis [25,26] with considerably fewer references to tryptophan metabolism [27].…”

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 .…”

Synthesis of l-Kynurenine and Homo-l-Kynurenine via an Aza-Fries Rearrangement

“…7 Some preclinical studies suggest the involvement of KP in the pathophysiology of stroke and its potential as a pharmacological target for stroke and related complications. 8 It has been demonstrated that kynurenine is an endogenous ligand for the aryl hydrocarbon (AH) receptor. 9 More recently, it was established that some compounds formed during the KP might have either neuroprotective or neurotoxic properties, 1c and they have the potential to be used as specific biomarkers for patients diagnosed with amyotrophic lateral sclerosis.…”