dizocilpine-maleate and Asphyxia

Hypothermia induced after perinatal hypoxia-ischemia is partially protective. This study examined whether early treatment with the noncompetitive N-methyl-d-aspartate receptor antagonist, dizocilpine, can augment neuroprotection with delayed hypothermia after severe asphyxia in preterm fetal sheep at 0.7 weeks gestation (equivalent to 28-32 weeks in humans).. Fifty minutes after umbilical cord occlusion for 25 minutes, fetuses were randomized to either dizocilpine (2 mg/kg estimated fetal weight intravenously, then 0.07 mg/kg/h for 4 hours) and then after 5.5 hours to whole-body cooling to 3°C below baseline, or sham cooling, until 72 hours, and euthanized 7 days after umbilical cord occlusion.. Delayed hypothermia was associated with improved neuronal survival (P<0.02) and reduced microglia (P=0.004) and caspase-3-positive cells (P<0.01) compared with umbilical cord occlusion. Dizocilpine was associated with reduced microglia (P<0.05) but no effect on caspase-3 induction and improved survival only in CA1/2 (P<0.05) with no apparent additive effect with delayed hypothermia.. Early N-methyl-d-aspartate blockade and a clinical regime of delayed whole-body hypothermia provide nonadditive neuroprotection in the preterm brain.

Topics: Animals; Asphyxia; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fetus; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Neuroprotective Agents; Sheep

The present study investigated the effect of reventilation with 21% and 100% oxygen following asphyxia in newborn piglets on NMDA receptor binding characteristics, Na(+), K(+)-ATPase activity, and lipid peroxidation. After achieving a heart rate less than 60 beats per minute, asphyxiated piglets were reventilated with 21% oxygen or 100% oxygen. (3)[H]MK-801 binding showed the Bmax in the 21% and 100% groups to be 1.53 +/- 0.43 and 1.42 +/- 0.35 pmol/mg protein (p = ns). Values for Kd were 4.56 +/- 1.29 and 4.17 +/- 1.05 nM (p = ns). Na(+), K(+)-ATPase activity in the 21% and 100% groups were 23.5 +/- 0.9 and 24.4 +/- 3.9 micromol Pi/mg protein/h (p = ns). Conjugated dienes (0.05 +/- 0.02 vs. 0.07 +/- 0.03 micromol/g brain) and fluorescent compounds (0.54 +/- 0.05 vs. 0.78 +/- 0.19 microg quinine sulfate/g brain), were similar in both groups (p = ns). Though lipid peroxidation products trended higher in the 100% group, these data show that NMDA receptor binding and Na(+), K(+)-ATPase activity were similar following reventilation with 21% or 100% oxygen after a single episode of mild asphyxia.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Asphyxia; Brain; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Infant, Newborn; Oxygen; Oxygen Inhalation Therapy; Receptors, N-Methyl-D-Aspartate; Resuscitation; Sodium-Potassium-Exchanging ATPase

Exposure to severe hypoxia leads to delayed cerebral and peripheral hypoperfusion. There is evidence in the very immature brain that transient abnormal glutaminergic receptor activity can occur during this phase of recovery. We therefore examined the role of N-methyl-D-aspartate (NMDA) receptor activity in mediating secondary hypoperfusion in preterm fetal sheep at 70% of gestation. Fetuses received either sham asphyxia or asphyxia and were studied for 12 h recovery. The specific, non-competitive NMDA receptor antagonist dizocilpine maleate (2 mg kg-1 bolus plus 0.07 mg kg h-1i.v.) or saline (vehicle) was infused from 15 min after asphyxia until 4 h. In the asphyxia-vehicle group abnormal epileptiform EEG transients were observed during the first 4 h of reperfusion, the peak of which corresponded approximately to the nadir in peripheral and cerebral hypoperfusion. Dizocilpine significantly suppressed this activity (2.7+/-1.3 versus 11.2+/-2.7 counts min-1 at peak frequency, P<0.05) and markedly delayed and attenuated the rise in vascular resistance in both peripheral and cerebral vascular beds observed after asphyxia, effectively preventing the initial deep period of hypoperfusion in carotid blood flow and femoral blood flow (P<0.01). However, while continued infusion did attenuate subsequent transient tachycardia, it did not prevent the development of a secondary phase of persistent but less profound hypoperfusion. In conclusion, the present studies suggest that in the immature brain the initial phase of delayed cerebral and peripheral hypoperfusion following exposure to severe hypoxia is mediated by NMDA receptor activity. The timing of this effect in the cerebral circulation corresponds closely to abnormal EEG activity, suggesting a pathological glutaminergic activation that we speculate is related to evolving brain injury.

Topics: Animals; Asphyxia; Brain; Carotid Arteries; Cerebrovascular Circulation; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Femoral Artery; Fetal Hypoxia; Fetus; Gestational Age; Heart Rate, Fetal; Receptors, N-Methyl-D-Aspartate; Sheep; Time Factors; Umbilical Cord; Vascular Resistance

The accumulation of free fatty acid (FFA) in the brain occurs within minutes of anoxia, induced by exposing mice to a 100% N2 atmosphere. The rate of FFA release is high within the first minute and continues to increase moderately hereafter. FFA is apparently accumulated at the highest concentration in the cerebral hemispheres. The release of FFA can be inhibited partly by CNS depressants like N6-cyclopentyladenosine, pentobarbital, ethanol, or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3(2H)-one (THIP). Antiadrenergic compounds such as reserpine, clondine, or prazosine were also found to be active. The N2 anoxia was initially and temporarily associated with motor excitation termed fight and flight reaction. This behavior could be reduced by administration of N6-cyclopentyl-adenosine, pentobarbital, ethanol, reserpine, and prazosine, but not by THIP or clonidine. The glutamate antagonist MK-801 inhibited the fight and flight reaction, but did not affect the FFA accumulation. The data are consistent with the view that brain anoxia initially increases FFA by receptor-mediated polyphosphoinositide breakdown and that the alpha-1 adrenergic receptor is one of the receptors involved. The data also indicate that the fight and flight reaction is dissociated from the events that lead to FFA release, and may involve the stimulation of glutaminergic NMDA receptors.

Topics: Anesthetics; Animals; Asphyxia; Brain Chemistry; Central Nervous System Depressants; Dizocilpine Maleate; Escape Reaction; Fatty Acids, Nonesterified; Female; Hypoxia, Brain; Mice; Receptors, N-Methyl-D-Aspartate; Sympatholytics