Competitive N-methyl-D-aspartate receptor blockade reduces brain injury following transient focal ischemia in cats.

Nishikawa, Toshiaki; Kirsch, Jeffrey R.; Koehler, Raymond C.; Miyabe, Masayuki; Traystman, Richard J.

doi:10.1161/01.str.25.11.2258

Cited by 26 publications

(13 citation statements)

References 49 publications

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“…Furthermore, the deleterious effects of the administration of this agent (GPI 3000) on mortality are strongly dose dependent. Surprisingly, these results differ from those obtained with focal 5 and incomplete global 12 cerebral ischemias and suggest that systemic effects of NMDA receptor antagonists may influence recovery.…”

Section: Discussioncontrasting

confidence: 92%

“…[1][2][3] Excessive activation of NMDA receptors under conditions of energy substrate depletion leads to neuronal death. 4,5 Treatment of focal ischemia with a noncompetitive NMDA receptor antagonist such as MK-801 can reduce neuronal injury, albeit with significant adverse effects. 6,7 Although non-NMDA (glutamate) receptor antagonists have been efficacious in global cerebral ischeSee Editorial Comment, page 829 mia, 8 NMDA receptor antagonism has yielded variable results.…”

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confidence: 99%

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Treatment With the Competitive NMDA Antagonist GPI 3000 Does Not Improve Outcome After Cardiac Arrest in Dogs

Helfaer

Ichord

Martin

et al. 1998

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Background and Purpose-We previously showed that treatment with a competitive N-methyl-D-aspartate (NMDA) receptor antagonist GPI-3000 (GPI) improved short-term physiological recovery after incomplete global cerebral ischemia complicated by dense acidosis. We tested the hypothesis that GPI administered after resuscitation from cardiac arrest would improve a more long-term recovery as measured by neurobehavioral assessment and neuropathology 4 days after resuscitation. Methods-Anesthetized dogs were subjected to 7 minutes of cardiac arrest followed by vest cardiopulmonary resuscitation.Neurobehavioral outcomes were scored daily on a score ranging from 0 (normal) to 500 (worst). On the fourth day, the animals were killed, and neuropathology was evaluated in a blinded manner in the hippocampus and the neocortex by hematoxylin and eosin staining and by determination of percentage of injured neurons. Three groups of animals were treated in a randomized, blinded protocol with either saline (SAL), low-dose GPI (5 mg/kg followed by 1 mg/kg per hour for 2 hours), or high-dose GPI (25 mg/kg, followed by 5 mg/kg per hour for 2 hours). Results-The mortality rate was higher in animals receiving GPI than in saline-treated control animals (4 of 15 deaths in SAL, 6 of 15 in the low-dose GPI group, and 9 of 18 in the high-dose GPI group). Neurobehavioral scores were depressed in GPI-treated animals compared with saline-treated control animals in a dose-dependent manner, with 96-hour scores of essentially normal (9Ϯ2) in saline-treated animals compared with those animals with significant impairment (181Ϯ47) treated with high-dose GPI. Neuropathological damage in the neocortex was most severe in GPI-treated animals, with the percentage of injured neurons dependent on the dose: 8.3%Ϯ2.7% SAL, 13.2%Ϯ6.4% low-dose GPI, and 39.4%Ϯ10.1%, high-dose GPI. CA1 neuronal damage was severe regardless of treatment. Conclusions-Contrary to results seen in experimental global and focal cerebral ischemia, in which NMDA receptor antagonism may improve responses to injury, receptor antagonism with GPI does not improve brain outcome after cardiac arrest and resuscitation in the dog. Behavioral and histological outcomes both were worsened by GPI treatment at two doses, and mortality was higher relative to saline control treatment. We speculate that systemic drug effects, as well as potential neurotoxicity of the drug under ischemic conditions, may be responsible for the deleterious outcomes observed in our cardiac arrest model. (Stroke. 1998;29:824-829.)

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confidence: 92%

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confidence: 99%

Treatment With the Competitive NMDA Antagonist GPI 3000 Does Not Improve Outcome After Cardiac Arrest in Dogs

Helfaer

Ichord

Martin

et al. 1998

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“…For the reason that the hypometabolism after the reperfusion was inhibited significantly in the treatment groups in the ischaemic penumbra, we suppose that inhibition of excitatory amino acid reduced focal ischaemic damage [16,19,31] by inhibiting the ischaemia-induced glucose hypermetabolism. The possibility of treatment by NMDA receptor antagonist is indicated in order to delay the ischaemic neuron damage until the restoration of the blood flow.…”

Section: The Effect Of Mk-801 Administrationmentioning

confidence: 91%

The sequential change of local cerebral blood flow and local cerebral glucose metabolism after focal cerebral ischaemia and reperfusion in rat and the effect of MK-801 on local cerebral glucose metabolism

et al. 1997

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In order to investigate the time course change of local cerebral blood flow (1CBF) and local cerebral glucose metabolism (ICGM) and the effect of MK-801 (dizocilpine), an NMDA receptor antagonist on glucose metabolism in a middle cerebral artery occlusion-reperfusion model, 14C-Iodo-antipyrine and 14C-Deoxyglucose autoradiographic method have been used. The 1CBF was reduced to 0-10% of the control level in the ischaemic core and to 12-40% in the ischaemic penumbra between 60 and 120 min after the onset of the ischaemia. In the ischaemic core, the marked hyperfusion appeared at 15 min and maintained about 30 to 45 min following reperfusion. In the ischaemic penumbra, the hyperfusion during reperfusion was not found. Hypermetabolism occurred at 30 min and reached to the peak at 60 min after the middle cerebral artery (MCA) occlusion both in the ischaemic core and in the penumbra. The shift from hyper- to hypometabolism was observed during the ischaemia. The reperfusion following 2 hours of MCA occlusion facilitated the decrease of cerebral glucose metabolism in the ischaemic region. The pretreatment of MK-801 (0.4 mg/kg) inhibited both increased glucose metabolism during the ischaemia and decreased glucose metabolism during the reperfusion. The effect of limiting decreased glucose metabolism during the reperfusion by MK-801 was remarkable in the ischaemic penumbra. These findings support the hypothesis that excitation-induced hypermetabolism play a major role in the ischaemic insult following focal cerebral vascular occlusion.

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“…This results in an erroneous determination of the ischemic area with the use of computerassisted image analyzing systems. 8 The same problem, based on a lack of difference between the OD of normal white matter and ischemic brain tissue, is also typical of nitroblue See Editorial Comment, page 1140 tetrazolium (NBT) 9 -11 and 2,3,5-triphenyltetrazolium hydrochloride (TTC) 7,[12][13][14][15] stains. These stains are also commonly used for the delineation of ischemic brain tissue.…”

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Early Delineation of Ischemic Tissue in Rat Brain Cryosections by High-Contrast Staining

Vogel

Möbius

Kuschinsky

1999

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Background and Purpose-After short periods of ischemia, commonly used staining methods yield only moderate differences in optical contrast between normal and damaged brain tissue when gray-scale images are used for computer-assisted image analysis. We describe a high-contrast silver infarct staining (SIS) method that allows an early delineation of ischemic tissue as soon as 2 hours after middle cerebral artery occlusion (MCAO) in rat brain cryosections. Methods-Rats were subjected to permanent MCAO for 2, 4, 6, and 48 hours. The optical densities were quantified in nonischemic white and gray matter and in damaged tissue from gray-scale images of serial sections with the use of a video camera-based image analyzing system. SIS, hematoxylin-eosin, Nissl, and nitroblue tetrazolium stainings were performed in cryosections, and 2,3,5-triphenyltetrazolium hydrochloride (TTC) staining was performed in unfrozen vibratome sections. In addition, the range of reduced cerebral blood flow (CBF) in areas demarcated by SIS was determined in iodo[ 14 C]antipyrine autoradiograms of adjacent cryosections. Results-At all times after MCAO, only SIS showed significantly (PϽ0.01) lower optical densities in damaged than in normal brain tissue for both white and gray matter. TTC staining was as effective as SIS 6 and 48 hours after MCAO. The tightest correlation between areas of reduced SIS and of reduced CBF was found at a mean ischemic CBF of 22.3 mL/100 g per minute. This corresponds to a CBF range of 0 to 44 mL/100 g per minute in areas of reduced SIS. Conclusions-In contrast to other staining methods, SIS allows a reliable delineation of ischemic brain tissue (core plus penumbra) from nonischemic white and gray matter of rat brain cryosections as soon as 2 hours after MCAO. (Stroke. 1999;30:1134-1141.)

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Competitive N-methyl-D-aspartate receptor blockade reduces brain injury following transient focal ischemia in cats.

Cited by 26 publications

References 49 publications

Treatment With the Competitive NMDA Antagonist GPI 3000 Does Not Improve Outcome After Cardiac Arrest in Dogs

Treatment With the Competitive NMDA Antagonist GPI 3000 Does Not Improve Outcome After Cardiac Arrest in Dogs

The sequential change of local cerebral blood flow and local cerebral glucose metabolism after focal cerebral ischaemia and reperfusion in rat and the effect of MK-801 on local cerebral glucose metabolism

Early Delineation of Ischemic Tissue in Rat Brain Cryosections by High-Contrast Staining

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