Role of the NMDA receptor and iron on free radical production and brain damage following transient middle cerebral artery occlusion

Im, Doo Soon; Jeon, Jeong Wook; Lee, Jin Soo; Won, Seok Joon; Cho, Sung Ig; Lee, Yong Beom; Gwag, Byoung Joo

doi:10.1016/j.brainres.2012.03.025

Cited by 20 publications

(18 citation statements)

References 41 publications

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“…Previous reports suggest that iron neurotoxicity is mainly due to glutamate excitotoxicity (Munoz et al, 2011; Im et al, 2012). Hemin is an iron containing compound and iron is a direct product of hemin degradation and therefore we measured hemin-mediated changes in [Ca 2+ ] i .…”

Section: Resultsmentioning

confidence: 95%

Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity

Mohan

Glushakov

deCurnou

et al. 2013

Front. Mol. Neurosci.

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Although hemin-mediated neurotoxicity has been linked to the production of free radicals and glutamate excitotoxicity, the role of the prostaglandin E2 (PGE2)-EP1 receptor remains unclear. Activation of the EP1 receptor in neurons results in increased intracellular calcium levels; therefore, we hypothesize that the blockade of the EP1 receptor reduces hemin neurotoxicity. Using postnatal primary cortical neurons cultured from wild-type (WT) and EP1−/− mice, we investigated the EP1 receptor role in hemin neurotoxicity measured by lactate dehydrogenase (LDH) cell survival assay. Hemin (75 μM) induced greater release of LDH in WT (34.7 ± 4.5%) than in EP1−/− (27.6 ± 3.3%) neurons. In the presence of the EP1 receptor antagonist SC-51089, the hemin-induced release of LDH decreased. To further investigate potential mechanisms of action, we measured changes in the intracellular calcium level [Ca2+]i following treatment with 17-phenyl trinor PGE2 (17-pt-PGE2) a selective EP1 agonist. In the WT neurons, 17-pt-PGE2 dose-dependently increased [Ca2+]i. However, in EP1−/− neurons, [Ca2+]i was significantly attenuated. We also revealed that hemin dose-dependently increased [Ca2+]i in WT neurons, with a significant decrease in EP1−/− neurons. Both 17-pt-PGE2 and hemin-induced [Ca2+]i were abolished by N-methyl-D-aspartic (NMDA) acid receptor and ryanodine receptor blockers. These results suggest that blockade of the EP1 receptor may be protective against hemin neurotoxicity in vitro. We speculate that the mechanism of hemin neuronal death involves [Ca2+]i mediated by NMDA acid receptor-mediated extracellular Ca2+ influx and EP1 receptor-mediated intracellular release from ryanodine receptor-operated Ca2+ stores. Therefore, blockade of the EP1 receptor could be used to minimize neuronal damage following exposure to supraphysiological levels of hemin.

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Section: Resultsmentioning

confidence: 95%

Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity

Mohan

Glushakov

deCurnou

et al. 2013

Front. Mol. Neurosci.

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“…In particular various ion channels including GABA, NMDA, acetylcholine, Na + , K + and Ca 2+ channels were reported to be sensitive toward nanomolar concentration of zinc and copper (39) and dysregulation of Ca 2+ was also correlated with the mechanism of zinc-induced neurotoxicity (43). Evidence on the role of L-type Ca 2+ channels in iron-induced neurotoxicity (44) or of mitochondrial Ca 2+ uniporter in the prevention of mitochondria dysfunction caused by iron overload was recently emphasized (45). As a whole our data add some substantial knowledge into the cellular mechanisms of I/R injury-induced neuronal death.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Grape Seed and Skin Extract on Cerebral Ischemia in Rat: Implication of Transition Metals

Kadri

Smine

Mohamed

et al. 2014

International Journal of Stroke

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Ischemic stroke is a leading cause of long lasting disability in humans and oxidative stress an important underlying cause. The present study aims to determine the effect of short term (seven-days) administration of high dosage grape seed and skin extract (GSSE 2.5 g/kg) on ischemia/reperfusion (I/R) injury in a rat model of global ischemia. Ischemia was induced by occlusion of the common carotid arteries for 30 min followed by one-hour reperfusion on control or GSSE treated animals. I/R induced a drastic oxidative stress characterized by high lipid and protein oxidation, a drop in antioxidant enzyme defenses, disturbed transition metals as free iron overload and depletion of copper, zinc and manganese as well as of associated brain enzyme activities as glutamine synthetase and lactate dehydrogenase. I/R also induced NO and calcium disruption and an increase in calpain activity, a calcium-sensitive cysteine protease. Interestingly, almost all I/R-induced disturbances were prevented by GSSE pretreatment as oxidative stress, transition metals associated enzyme activities, brain damage size and histology. Owing to its antioxidant potential, high dosage GSSE protected efficiently the brain against ischemic stroke and should be translated to humans.

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“…MK-801 is a potent anticonvulsant and dissociative anesthetic; however, MK-801 is not used clinically because it has been shown to promote the development of brain lesions in rats (Olney et al 1989). It is well known for its neuroprotective effect in animal models of stroke, trauma, Parkinsonism and Alzheimer's disease (Jeong et al 2010;Im et al 2012;Wang et al 2014). In rats, MK-801 induces a characteristic behavioral syndrome with ataxia, stereotypic behavior and hyperlocomotion (Suetake-Koga et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Synthase Modulates the Antihyperalgesic Effect of the NMDA Receptor Antagonist MK-801 on Carrageenan-Induced Inflammatory Pain in Rats

Srebro

Vučković

Vujović

et al. 2014

Tohoku J. Exp. Med.

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The N-methyl-d-aspartate (NMDA) receptor, an ionotropic glutamate receptor, may play a significant role in the development and maintenance of an inflammatory pain. Activation of NMDA receptors may cause nitric oxide (NO) release through activation of NO synthase (NOS). MK-801, a noncompetitive NMDA receptor antagonist is commonly used as a neuropharmacological tool. The interaction between MK-801 and NOS in the inflammatory pain has not been evaluated before. We investigated whether MK-801 affects inflammatory pain and whether NOS modulates the effect of MK-801. Carrageenan-induced hyperalgesia was evaluated by measuring the withdrawal response to mechanical stimuli, using an electronic version of the von Frey anesthesiometer in Wistar rats. MK-801 given subcutaneously (0.5-20 μg/kg) or intraplantarly (0.1 and 0.15 μg/paw) significantly reduced mechanical hyperalgesia. Intraplantarly given MK-801 exerted a local antihyperalgesic effect, because when applied to the contralateral side it did not reduce mechanical sensitivity in the ipsilateral side. N-nitro-L-arginine methyl ester hydrochloride (5 and 10 mg/kg), a non-selective NOS inhibitor, significantly reduced the effects of MK-801. N-ω -Propyl-L-arginine hydrochloride (0.5-2 mg/kg), a selective inhibitor of neuronal NOS, increased the antihyperalgesic effect of MK-801, whereas S-methylisothiourea (5-15 μg/kg), a selective inhibitor of inducible NOS, lowered the antihyperalgesic effect of MK-801. Importantly, each NOS inhibitor given alone did not affect carrageenaninduced hyperalgesia. In conclusion, MK-801 is effective against inflammatory pain and its antihyperalgesic effect is modulated in a different ways by NOS, being enhanced by a neuronal NOS inhibitor but reduced by an inducible NOS inhibitor.

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Role of the NMDA receptor and iron on free radical production and brain damage following transient middle cerebral artery occlusion

Cited by 20 publications

References 41 publications

Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity

Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity

Protective Effect of Grape Seed and Skin Extract on Cerebral Ischemia in Rat: Implication of Transition Metals

Nitric Oxide Synthase Modulates the Antihyperalgesic Effect of the NMDA Receptor Antagonist MK-801 on Carrageenan-Induced Inflammatory Pain in Rats

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