Overexpression of kynurenic acid in stroke: An endogenous neuroprotector?

Mangas, A.; Yajeya, Javier; González, N. Boronat; Ruiz, I.; Duleu, S.; Geffard, M.; Coveñas, Rafael

doi:10.1016/j.aanat.2017.01.002

Cited by 8 publications

(36 citation statements)

References 24 publications

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“…A transient middle artery cerebral occlusion (50-55 min) was carried out by using a rounded tip monofilament. 16,17 …”

Section: Methodsmentioning

confidence: 99%

“…As previously reported, 16,17,22 the following protocol was conducted: 10 mg of the corresponding small molecule ( e.g ., kynurenine) were dissolved in methanol or in sodium acetate solution (solution 1); later, 20 mg of BSA were dissolved in water or in sodium acetate solution (solution 2). Then, solution 1 containing the small molecule ( e.g.…”

Section: Methodsmentioning

confidence: 99%

“…After that, the linkage of the small molecule ( e.g ., kynurenine) to BSA was over and the immunogenic compounds ( e.g ., kynurenine-BSA) were purified using dialysis membranes (cut-off limits 12-16 KDa). 16,17,22 …”

Section: Methodsmentioning

confidence: 99%

“…After the second immunization, serum samples were collected and antisera were pre-purified and tested by ELISA. 16,17,22,23 Once the polyclonal antibodies were characterized, a fusion of mice splenocytes and SP2/O/Ag myeloma cells was conducted. After the spleen dissection, the following steps were performed in vitro .…”

Section: Methodsmentioning

confidence: 99%

“…Thus, in an experimental model of stroke (single transient middle cerebral artery occlusion) 16,17 and using immunohistochemical techniques, we studied the expression of inflammatory ( e.g ., CD45, CD11b), oxidative ( e.g ., NO-tryptophan, NO 2 -tyrosine) and IDO pathway ( e.g ., kynurenic acid, 3-hydroxy anthranilic acid) markers in the rat brain after treatment with Gemst. Moreover, for this purpose, we have developed for the first time several highly specific monoclonal antibodies directed against some of these markers.…”

Section: Introductionmentioning

confidence: 99%

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Gemst: a taylor-made combination that reverts neuroanatomical changes in stroke

Mangas

Yajeya

González³

et al. 2017

Eur J Histochem

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In a single transient middle cerebral artery occlusion model of stroke and using immunohistochemical techniques, the effects of a new therapeutic approach named Gemst (a member of the Poly-LLysine innovative therapies) have been studied in the rat brain. The expression of inflammatory (CD45, CD11b), oxidative (NO-tryptophan, NO2-tyrosine) and indoleamine 2, 3-dioxygenase pathway (kynurenic acid, 3-hydroxy anthranilic acid) markers has been evaluated in early and late phases of stroke. For this purpose, we have developed eight highly specific monoclonal antibodies directed against some of these markers. In the early phase (3 and 5 days of the stroke, we observed no effect of Gemst treatment (7.5 mg/day, subcutaneously for 3, 5 days). In the late phase (21 days) of stroke and exclusively in the ipsilateral side of non-treated animals an overexpression of kynurenic acid, 3- hydroxy anthranilic acid, CD45, CD11b, GFAP and ionized calcium-binding adapter molecule 1 (IBA-1) was found. In treated animals, the overexpression of the four former markers was completely abolished whereas the overexpression of the two latter ones was decreased down to normal levels. Gemst reversed the pathological conditions of stroke to normal situations. Gemst exerts a multifunctional action: down-regulates the indoleamine 2, 3-dioxygenase pathway and abolishes brain infiltration, microglial activation and gliosis. Moreover, Gemst has no effect on the expression of doublecortin, a protein involved in neuronal migration. Gemst could be a new drug for the treatment of stroke since it reverses the pathological findings of stroke and normalizes brain tissue conditions following the ischemic insult.

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“…A transient middle artery cerebral occlusion (50-55 min) was carried out by using a rounded tip monofilament. 16,17 …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Gemst: a taylor-made combination that reverts neuroanatomical changes in stroke

Mangas

Yajeya

González³

et al. 2017

Eur J Histochem

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

et al. 2019

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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.

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The Mechanism of the Neuroprotective Effect of Kynurenic Acid in the Experimental Model of Neonatal Hypoxia–Ischemia: The Link to Oxidative Stress

et al. 2021

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The over-activation of NMDA receptors and oxidative stress are important components of neonatal hypoxia–ischemia (HI). Kynurenic acid (KYNA) acts as an NMDA receptor antagonist and is known as a reactive oxygen species (ROS) scavenger, which makes it a potential therapeutic compound. This study aimed to establish the neuroprotective and antioxidant potential of KYNA in an experimental model of HI. HI on seven-day-old rats was used as an experimental model. The animals were injected i.p. with different doses of KYNA 1 h or 6 h after HI. The neuroprotective effect of KYNA was determined by the measurement of brain damage and elements of oxidative stress (ROS and glutathione (GSH) level, SOD, GPx, and catalase activity). KYNA applied 1 h after HI significantly reduced weight loss of the ischemic hemisphere, and prevented neuronal loss in the hippocampus and cortex. KYNA significantly reduced HI-increased ROS, GSH level, and antioxidant enzyme activity. Only the highest used concentration of KYNA showed neuroprotection when applied 6 h after HI. The presented results indicate induction of neuroprotection at the ROS formation stage. However, based on the presented data, it is not possible to pinpoint whether NMDA receptor inhibition or the scavenging abilities are the dominant KYNA-mediated neuroprotective mechanisms.

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Overexpression of kynurenic acid in stroke: An endogenous neuroprotector?

Cited by 8 publications

References 24 publications

Gemst: a taylor-made combination that reverts neuroanatomical changes in stroke

Gemst: a taylor-made combination that reverts neuroanatomical changes in stroke

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

The Mechanism of the Neuroprotective Effect of Kynurenic Acid in the Experimental Model of Neonatal Hypoxia–Ischemia: The Link to Oxidative Stress

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