Posthypoxic treatment with MK‐801 reduces hypoxic‐ischemic damage in the neonatal rat

Hattori, Haruo; Morin, Alexandre; Schwartz, Phillip H.; Fujikawa, Denson G.; Wasterlain, Claude G.

doi:10.1212/wnl.39.5.713

Cited by 148 publications

(47 citation statements)

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“…Effective levels of NOARG would not be reached because the peritoneal vascular beds are vasoconstricted and absorption is slow. The lack of posthypoxic effect of the NO synthase inhibitor is not in accord with the neuroprotective effect of posthypoxic treatment with the NMDA receptor antagonist, MK-801, in another neonatal rat model of hypoxic-ischemic brain damage (4).…”

Section: Discussionmentioning

confidence: 87%

“…In the prehypoxic damage in immature rats is identical in appearance and time treatment group (group 1, n = 12 pairs), 2 mdkg of NOARG course to the cfiotoxic reaction to NMDA (3). MK-801 [(+)-5-(Sigma Chemical CO., St. Louis, MO) was administered intramethyl-10,11-dihydro-5H-dibenzo[a1d]cyclohepten-5, 10-imine peritoneally 1.5 h before the h~x i c insult-The reason why we maleate], a noncompetitive NMDA antagonist, protects against chose the dose of 2 mdkg is that, in preliminary experiments, h xic-ischemic brain damage in neonatal rats (4 group (group 2, n = 12 pairs), 2 mg/kg of NOARG was given immediately after the cessation of hypoxia. Each experimental animal received NOARG dissolved in normal saline (5 mllkg), and its paired littermate was administered the same volume of normal saline.…”

Section: Abbreviationsmentioning

confidence: 99%

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Inhibitor of Nitric Oxide Synthesis Reduces Hypoxic-Ischemic Brain Damage in the Neonatal Rat

et al. 1994

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ABSTRACI'. We evaluated the neuroprotective effect of lium in the conversion of L-arginine to L-citrulline by the enzyme the nitric oxide synthesis inhibitor, NC-nitro-L-arginine in NO synthase ( 9 , whose activity has also been reported in forea neonatal hypoxic-ischemic rat model. Unilateral hypoxic-brain homogenates (6). NMDA stimulates NO synthesis (7), and ischemic iqjury was produced in the brain of 7-dsld rats NO mediates glutamate neurotoxicity in vitro (8). NOARG, an using a combition of a common carotid artery ligation analog of L-arginine, competitively inhibits the enzymatic forand a hypoxic (8% oxygen) exposure for 2.5 h. In our mation of NO both in cultured endothelial cells (9) and cerebellar experimental condition, rectal temperatures did not differ homogenates (lo), also prevents neurotoxicity induced by between NC-nitro-L-argininetreated and salineinjected NMDA in cortical cultures (8), and easily crosses the blood-brain pups. We killed the animals 72 h later and assessed the barrier (10). hypoxic-ischemic brain damage histologically. NG-nitro-L-Contradictory reports concerning the possible neuroprotective 9 nine (2 mg/kg) administered intraperitoneally 1.5 h effect of NO synthesis inhibitors in adult models (1 1-16) be ore hypoxia resulted in 77% reduction of the infarcted prompted us to investigate whether NO was related to the genesis hemispheric volume and 87% reduction of the infarcted of cerebral hypoxic-ischemic brain damage in neonates. Sevenstriatal volume compared to saline injected controls. P -d-old rats were subjected to unilateral carotid artery ligation nitro-L-arginine given 1.5 h before the insult also signifi-followed by hypoxic exposure. This neonatal rat model shows cantly prevented hypoxic-ischemic damage in the five hip-infarction of the cerebral hemisphere ipsilateral to the carotid pocrunpal structures examined, dentate gyruq CA4, CA3, artery ligation (17), and has been frequently used to investigate CAI, and subiculum. NG-nitro-L-arginine administered im-the pathogenesis of cerebral hypoxia ischemia (for review see mediately after hypoxia did not prevent hypoxic-ischemic Refs. 1 and 18). We investigated the neuroprotective effect of brain damage. These results indicate that nitric oxide plays NOARG administered before and after a hypoxic insult. a key role in producing neonatal hypoxic-ischemic brain damage. (Pediatr RPS 35: 10-14,1994) MATERIALS AND METHODS AbbreviationsWe used the method of Rice et al. (17) to produce hypoxicischemic brain damage in neonatal rats. On the day of surgery, NMDA, N-methyl-aspa art ate 7-d-old Std:Wister rat (Japan SLC, Inc.) littermates (the day of NO, nitric oxide birth is defined as d 1) were paired according to sex and body NOARC, NC-nitro-L-arginine weight (f0.5 g), each pair consisting of a pup assigned to NOARG treatment and a saline-injected control. If one member of a pair died, the other member was discarded. Under ether anesthesia, the left carotid artery was exposed through a midline neck incision, doubly ligated, and severed b...

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Section: Discussionmentioning

confidence: 87%

Section: Abbreviationsmentioning

confidence: 99%

Inhibitor of Nitric Oxide Synthesis Reduces Hypoxic-Ischemic Brain Damage in the Neonatal Rat

et al. 1994

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“…However, most of the H-I-induced brain injury in P7 rats can be blocked by pretreatment with the NMDAR antagonist, MK801 (13). This result suggests that glutamate toxicity in the setting of neonatal H-I initiates both necrotic and apoptotic cell-death pathways (13,31). Further, it has been shown that necrosis is the cell-death pathway that is used immediately after the H-I in neonates and after glutamate challenges in cortical cultures (10,43,46).…”

Section: Discussionmentioning

confidence: 98%

“…H-I-induced brain injury in P7 rats can be blocked by pretreatment with the NMDA receptor (NMDAR) antagonist, MK801 (13,31). This finding suggests that glutamate-mediated toxicity via NMDARs in the setting of neonatal H-I initiates cell death with both necrotic and apoptotic features.…”

Section: Cytnmnat1 Protects Neuronal Processes and Cell Bodies Againstmentioning

confidence: 98%

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Verghese

Sasaki

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxic-ischemic (H-I) injury to the developing brain is a significant cause of morbidity and mortality in humans. Other than hypothermia, there is no effective treatment to prevent or lessen the consequences of neonatal H-I. Increased expression of the NAD synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) has been shown to be neuroprotective against axonal injury in the peripheral nervous system. To investigate the neuroprotective role of Nmnat1 against acute neurodegeneration in the developing CNS, we exposed wild-type mice and mice overexpressing Nmnat1 in the cytoplasm (cytNmnat1-Tg mice) to a well-characterized model of neonatal H-I brain injury. As early as 6 h after H-I, cytNmnat1-Tg mice had strikingly less injury detected by MRI. CytNmnat1-Tg mice had markedly less injury in hippocampus, cortex, and striatum than wild-type mice as assessed by loss of tissue volume 7 d days after H-I. The dramatic protection mediated by cytNmnat1 is not mediated through modulating caspase3-dependent cell death in cytNmnat1-Tg brains. CytNmnat1 protected neuronal cell bodies and processes against NMDA-induced excitotoxicity, whereas caspase inhibition or B-cell lymphoma-extra large (Bcl-XL) protein overexpression had no protective effects in cultured cortical neurons. These results suggest that cytNmnat1 protects against neonatal HI-induced CNS injury by inhibiting excitotoxicity-induced, caspase-independent injury to neuronal processes and cell bodies. As such, the Nmnat1 protective pathway could be a useful therapeutic target for acute and chronic neurodegenerative insults mediated by excitotoxicity.

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“…11). Further evidence for the "excitotoxic" theory is provided by experiments that show that antagonists to NMDA can prevent cerebral ischemic injury (12)(13)(14).…”

mentioning

confidence: 99%

Effect of Experimental Escherichia coli Meningitis on Concentrations of Excitatory and Inhibitory Amino Acids in the Rabbit Brain: In Vivo Microdialysis Study

et al. 1993

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Posthypoxic treatment with MK‐801 reduces hypoxic‐ischemic damage in the neonatal rat

Cited by 148 publications

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Inhibitor of Nitric Oxide Synthesis Reduces Hypoxic-Ischemic Brain Damage in the Neonatal Rat

Inhibitor of Nitric Oxide Synthesis Reduces Hypoxic-Ischemic Brain Damage in the Neonatal Rat

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Effect of Experimental Escherichia coli Meningitis on Concentrations of Excitatory and Inhibitory Amino Acids in the Rabbit Brain: In Vivo Microdialysis Study

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