Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils

Gigler, Gábor; Szénási, Gábor; Simó, Annamária; Lévay, György; Hársing, László G.; Sas, Katalin; Vécsei, László; Toldi, József

doi:10.1016/j.ejphar.2007.02.029

Cited by 79 publications

(51 citation statements)

References 31 publications

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“…Accordingly, studies on the effect of L-Kyn are controversial. L-Kyn, apparently by elevating brain kynurenic acid levels, results in neuroprotection when administered before hypoxia/ischemia and N-methyl-daspartate lesions [40][41][42][43] ; conversely, and in agreement with our data, postischemic L-Kyn administration exacerbated acute neuronal damage after MCAO. 44 Therefore, direct actions of L-Kyn, without the involvement of its downstream metabolites, remained obscure.…”

Section: Discussionsupporting

confidence: 81%

L-Kynurenine/Aryl Hydrocarbon Receptor Pathway Mediates Brain Damage After Experimental Stroke

et al. 2014

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Background-Aryl hydrocarbon receptor (AhR) is a transcription factor that belongs to the basic helix-loop-helix PAS (PerArnt-Sim homology domain) family known to mediate the toxic and carcinogenic effects of xenobiotics. Interestingly, AhR is widely expressed in the central nervous system, but its physiological and pathological roles are still unclear. Methods and Results-To define the role of AhR in stroke, we used middle cerebral artery occlusion in mice and oxygenglucose deprivation in rat cortical neurons. The results presented here show that the ischemic insult increases total and nuclear AhR levels and AhR transcriptional activity in neurons in vivo and in vitro. We also show that AhR has a causal role in acute ischemic damage because pharmacological or genetic loss-of-function approaches result in neuroprotection. Inhibition of cAMP response element-binding protein-dependent signaling may participate in the deleterious actions of AhR. Finally, we have also found that L-kynurenine, a tryptophan metabolite with AhR agonistic properties, is an endogenous ligand that mediates AhR activation in the brain after middle cerebral artery occlusion. Conclusions-Our data demonstrate that an L-kynurenine/AhR pathway mediates acute brain damage after stroke and open new possibilities for the diagnosis and treatment of this pathology.

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Section: Discussionsupporting

confidence: 81%

L-Kynurenine/Aryl Hydrocarbon Receptor Pathway Mediates Brain Damage After Experimental Stroke

et al. 2014

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“…In the gerbil, the two-vessel occlusion model (occluding both common carotid arteries) is used because the posterior communicating arteries are not anatomically involved or are less anatomically involved, which results in better neuronal cell death in the hippocampus. A paucity of quantitative data on the infarct at 24 hr of reflow exists, because most of the reports are on 7 days of reflow and histological evaluation is made on the hippocampal CA1 sector (Gigler et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Most of the reports study effects after 7 days of reflow, and histological evaluation has been made on the hippocampal CA1 sector (Gigler et al, 2007). We chose to work on neurons because they are more sensitive to ischemia than glial cells (Plum, 1983).…”

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confidence: 99%

The neuronal apoptotic death in global cerebral ischemia in gerbil: Important role for sodium channel modulator

Brahma

Dohare

Varma

et al. 2008

J of Neuroscience Research

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Global ischemia was induced in gerbil by bilateral occlusion of the common carotid arteries for 5 min. Sodium ionophore monensin or sodium channel blocker tetrodotoxin (TTX) was administered at doses of 10 micorg/kg, i.p., 30 min before ischemia induction; the dose was repeated after 22 hr. Subsequently, brain infarct occurred, determined at 24 hr after occlusion. Large, well-demarcated infarcts were observed in both hemispheres, an important observation because it critically influences the interpretation of the data. Because nitric oxide (NO) production is thought to be related to ischemic neuronal damage, we examined increases in Ca(2+) influx, which lead to the activation of nitric oxide synthase (NOS). Then we evaluated the contributions of neuronal NOS, endothelial NOS, and inducible NOS to NO production in brain cryosections. The cytosolic release of apoptogenic molecules like cytochrome c and p53 were confirmed after 24 hr of reflow. TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) labeling detected the apoptotic cells, which were confirmed in neuron-rich cell populations. After 24 hr, all the ischemic changes were amplified by monensin and significantly attenuated by TTX treatment. Additionally, the nesting behavior and histological outcomes were examined after 7 day of reflow. The neuronal damage in the hippocampal area and significant decrease in nesting scores were observed with monensin treatment and reduced by TTX pretreatment after day 7 of reflow. To our knowledge, this report is the first to highlight the involvement of the voltage-sensitive Na(+) channel in possibly regulating in part NO system and apoptosis in a cytochrome c-dependent manner in global ischemia in the gerbil, and thus warrants further investigation.

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“…Therefore, elevation of brain KYNA level, either by administration of L-KYN or pharmacological manipulation of the availability of the kynurenine pathway enzymes, has become an attractive strategy to attenuate neuroinflammatory responses and to protect against glutamate induced excitotoxicity associated with ischemic brain injury (Tan et al, 2012;Vécsei et al, 2013). Accordingly, we and our collaborators achieved neuroprotection by the administration of L-KYN sulfate (L-KYNs) in experimental models of neurodegenerative diseases and ischemic stroke (Gigler et al, 2007;Németh et al, 2004;Vámos et al, 2009). In these studies, neuroprotection was achieved partly by the administration of 300 mg/bwkg LKYNs.…”

Section: Introductionmentioning

confidence: 99%

Systemic administration of l -kynurenine sulfate induces cerebral hypoperfusion transients in adult C57Bl/6 mice

Varga

Menyhárt

Puskás

et al. 2017

Microvascular Research

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Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils

Cited by 79 publications

References 31 publications

L-Kynurenine/Aryl Hydrocarbon Receptor Pathway Mediates Brain Damage After Experimental Stroke

L-Kynurenine/Aryl Hydrocarbon Receptor Pathway Mediates Brain Damage After Experimental Stroke

The neuronal apoptotic death in global cerebral ischemia in gerbil: Important role for sodium channel modulator

Systemic administration of l -kynurenine sulfate induces cerebral hypoperfusion transients in adult C57Bl/6 mice

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