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

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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NMDA Receptor–Dependent Increase of Cerebral Glucose Utilization after Hypoxia–Ischemia in the Immature Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199609000-00026 ◽

1996 ◽

Vol 16 (5) ◽

pp. 1005-1013 ◽

Cited By ~ 31

Author(s):

Eric Gilland ◽

Henrik Hagberg

Keyword(s):

Nmda Receptor ◽

Glucose Utilization ◽

Neuroprotective Effect ◽

Nmda Receptor Antagonist ◽

Immature Rat ◽

Mk 801 ◽

Cerebral Glucose Utilization ◽

Hypoxia Ischemia ◽

Dg Method ◽

Old Rats

Post-treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 reduces hypoxic–ischemic brain injury in immature animals. To elucidate possible mechanisms, cerebral glucose utilization (CMRglc) and cerebral blood flow (CBF) were measured 1–5 h after hypoxia–ischemia and administration of MK-801 in 7-day-old rats. After 100 min of unilateral hypoxia–ischemia, half of the pups were injected with MK-801. CMRglc was assessed by the [14C]deoxyglucose (2-DG) method. The brains were analyzed either by autoradiography or for energy metabolites and chromatographic separation of 2-DG-6-phosphate and 2-DG. CBF was measured by the autoradiographic [14C]iodoantipyrine method. Mean CMRglc in the cerebral cortex was increased ipsilaterally after hypoxia–ischemia to 15 ± 3.3 μmol 100 g−1 min−1 ( p < 0.01) and areas with CMRglc >20 μmol 100 g−1 min−1 amounted to 8.0 ± 7.7 mm2 in the ipsilateral hemisphere compared with 1.2 ± 1.6 mm2 contralateral ( p < 0.001). Treatment with MK-801 decreased CMRglc bilaterally ( p < 0.05) and reduced ipsilateral areas with increased CMRglc by 64% ( p < 0.01). CBF was unaltered after hypoxia–ischemia and by MK-801 treatment. In conclusion, regional glucose hyper-utilization in the parietal cortex after hypoxia–ischemia was attenuated by MK-801; this may have relevance to the neuroprotective effect of NMDA-receptor antagonists in this model.

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Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia

Autophagy ◽

10.4161/auto.6.3.11261 ◽

2010 ◽

Vol 6 (3) ◽

pp. 366-377 ◽

Cited By ~ 170

Author(s):

Silvia Carloni ◽

Silvia Girelli ◽

Claudia Scopa ◽

Giuseppe Buonocore ◽

Mariangela Longini ◽

...

Keyword(s):

Neuroprotective Effect ◽

Neonatal Hypoxia ◽

Hypoxia Ischemia

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Experimental neonatal hypoxia ischemia causes long lasting changes of oxidative stress parameters in the hippocampus and the spleen

Journal of Perinatal Medicine ◽

10.1515/jpm-2017-0070 ◽

2018 ◽

Vol 46 (4) ◽

pp. 433-439 ◽

Cited By ~ 8

Author(s):

Felipe Kawa Odorcyk ◽

Janaína Kolling ◽

Eduardo Farias Sanches ◽

Angela T.S. Wyse ◽

Carlos Alexandre Netto

Keyword(s):

Oxidative Stress ◽

Wistar Rat ◽

Mortality And Morbidity ◽

Neonatal Hypoxia ◽

Oxidative Stress Parameters ◽

Rat Pups ◽

Hypoxia Ischemia ◽

Anti Oxidant ◽

Enzyme Superoxide Dismutase ◽

Stress Parameters

Abstract Neonatal hypoxia ischemia (HI) is the main cause of mortality and morbidity in newborns. The mechanisms involved in its progression start immediately and persist for several days. Oxidative stress and inflammation are determinant factors of the severity of the final lesion. The spleen plays a major part in the inflammatory response to HI. This study assessed the temporal progression of HI-induced alterations in oxidative stress parameters in the hippocampus, the most affected brain structure, and in the spleen. HI was induced in Wistar rat pups in post-natal day 7. Production of reactive oxygen species (ROS), and the activity of the anti oxidant enzyme superoxide dismutase and catalase were assessed 24 h, 96 h and 38 days post-HI. Interestingly, both structures showed a similar pattern, with few alterations in the production of ROS species up to 96 h often combined with an increased activity of the anti oxidant enzymes. However, 38 days after the injury, ROS were at the highest in both structures, coupled with a decrease in the activity of the enzymes. Altogether, present results suggest that HI causes long lasting alterations in the hippocampus as well as in the spleen, suggesting a possible target for delayed treatments for HI.

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Prevention by the NMDA receptor antagonist, MK801 of neuronal loss produced by tetanus toxin in the rat hippocampus

British Journal of Pharmacology ◽

10.1111/j.1476-5381.1990.tb14156.x ◽

1990 ◽

Vol 101 (4) ◽

pp. 776-780 ◽

Cited By ~ 30

Author(s):

G. Bagetta ◽

G. Nisticò ◽

N.G. Bowery

Keyword(s):

Nmda Receptor ◽

Receptor Antagonist ◽

Tetanus Toxin ◽

Neuronal Loss ◽

Nmda Receptor Antagonist ◽

Rat Hippocampus

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Effect of hyperbaric oxygen on apoptosis in neonatal hypoxia-ischemia rat model

Journal of Applied Physiology ◽

10.1152/japplphysiol.00630.2003 ◽

2003 ◽

Vol 95 (5) ◽

pp. 2072-2080 ◽

Cited By ~ 59

Author(s):

John W. Calvert ◽

Changman Zhou ◽

Anil Nanda ◽

John H. Zhang

Keyword(s):

Hyperbaric Oxygen ◽

Caspase 3 ◽

Apoptotic Cell ◽

Neuroprotective Effect ◽

Parp Cleavage ◽

Artery Ligation ◽

Neonatal Hypoxia ◽

Rat Pups ◽

Hypoxia Ischemia ◽

Expression And Activity

We have previously demonstrated that a transient exposure to hyperbaric oxygen (HBO) attenuated the neuronal injury after neonatal hypoxia-ischemia. This study was undertaken to determine whether HBO offers this neuroprotection by reducing apoptosis in injured brain tissue. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% oxygen). Apoptotic cell death was examined in the injured cortex and hippocampus tissue. Caspase-3 expression and activity increased at 18 and 24 h after the hypoxia-ischemia insult. At 18-48 h, poly(ADP-ribose) polymerase (PARP) cleavage occurred, which reduced the band at 116 kDa and enhanced the band at 85 kDa. There was a time-dependent increase in the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells. A single HBO treatment (100% oxygen, 3 ATA for 1 h) 1 h after hypoxia reduced the enhanced caspase-3 expression and activity, attenuated the PARP cleavage, and decreased the number of TUNEL-positive cells observed in the cortex and hippocampus. These results suggest that the neuroprotective effect of HBO is at least partially mediated by the reduction of apoptosis.

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Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic–Ischemic Brain Injury

Molecules ◽

10.3390/molecules23081871 ◽

2018 ◽

Vol 23 (8) ◽

pp. 1871 ◽

Cited By ~ 14

Author(s):

Denis Silachev ◽

Egor Plotnikov ◽

Irina Pevzner ◽

Ljubava Zorova ◽

Anastasia Balakireva ◽

...

Keyword(s):

Oxidative Stress ◽

Targeted Delivery ◽

Cell Damage ◽

Brain Cell ◽

Neuroprotective Effects ◽

Neonatal Hypoxia ◽

Hypoxia Ischemia ◽

Causes Of Mortality ◽

High Production ◽

The Brain

Neonatal hypoxia–ischemia is one of the main causes of mortality and disability of newborns. To study the mechanisms of neonatal brain cell damage, we used a model of neonatal hypoxia–ischemia in seven-day-old rats, by annealing of the common carotid artery with subsequent hypoxia of 8% oxygen. We demonstrate that neonatal hypoxia–ischemia causes mitochondrial dysfunction associated with high production of reactive oxygen species, which leads to oxidative stress. Targeted delivery of antioxidants to the mitochondria can be an effective therapeutic approach to treat the deleterious effects of brain hypoxia–ischemia. We explored the neuroprotective properties of the mitochondria-targeted antioxidant SkQR1, which is the conjugate of a plant plastoquinone and a penetrating cation, rhodamine 19. Being introduced before or immediately after hypoxia–ischemia, SkQR1 affords neuroprotection as judged by the diminished brain damage and recovery of long-term neurological functions. Using vital sections of the brain, SkQR1 has been shown to reduce the development of oxidative stress. Thus, the mitochondrial-targeted antioxidant derived from plant plastoquinone can effectively protect the brain of newborns both in pre-ischemic and post-stroke conditions, making it a promising candidate for further clinical studies.

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