MK-801 does not protect against hypoxic-ischemic brain injury in piglets.

Abstract

Background and Purpose:The excitatory amino acid inhibitor MK-801 has been shown in many animals species to protect against hypoxic-ischemic brain injury. We sought to determine whether hypoxic-ischemic injury to the newborn pig's brain could be prevented by the use of MK-801.Methods: Hypoxic-ischemic injury to the brain was induced in forty 0-3-day-old piglets. They were randomized to receive either 3 mg/kg MK-801 (MK-801 group, n=20) or vehicle (control group, n=19) prior to insult At time 0, the carotid arteries were ligated and the blood pressure was reduced by one third by hemorrhage. At 15 minutes, inspired oxygen was reduced from 50% to 6%. At 30 minutes, inspired oxygen was changed to 100%, carotid ligatures were released, and the withdrawn blood was reinfused. An additional 14 piglets received 3 mg/kg MK-801 but not hypoxic-ischemic injury (drug-only group), and a final group of 11 piglets were subjected to only a sham operation (sham group).Results: Neurological examination scores at 24, 48, and 72 hours showed that MK-801 and drug-only piglets were significantly worse than the controls. Pathological examination of the brains at 72 hours showed significantly greater damage in the brains of the MK-801 and control pigs relative to the sham and drug-only groups. No differences were found between the control and the MK-801 groups. No differences were found between the sham and drug-only groups.Conclusions: MK-801, at a dose of 3 mg/kg, causes neurological dysfunction in piglets lasting at least 72 hours, but neither causes brain damage nor ameliorates the effects of hypoxicischemic injury to the brain of the newborn pig. (Stroke 1991^22:1270-1275)

Glucose given after hypoxic ischemia does not affect brain injury in piglets.

“…Neurological examination scores on sham-operated piglets (n = 10) not subjected to hypoxic ischemic injury were 20 [20,20] as previously reported. 8 Six (27%) of the piglets in the control group died before euthanasia, as did four (19%) of the glucose group (/ ) =NS). Pathological examination scores are shown in Table 2.…”

Hypoxia-Ischemia in the Neonatal Rat Brain: Histopathology after Post-Treatment with NMDA and Non NMDA Receptor Antagonists

“…2). This may, to some degree, be explained by the fact that higher doses of MK-801 caused sedation and abnormal behavior which may have in terfered with respiratory and cardiovascular compensatory mechanisms after HI and thereby counteracted neuroprotection [18,33], Mortality was somewhat higher (although not statistically significant) after treatment with 0.3 mg/kg of MK-801 than in control animals. This may have affected outcome as a higher loss of pups with severe brain injury may lead to a systematic underestimation of the brain damage in the MK-801 group.…”

“…neonatal rats [14,[16][17][18], fetal sheep [31] and newborn beagle puppies [32], but not all, e.g. newborn piglets [33]. MK-801 offered pronounced neu roprotection in lower doses than reported pre viously with posttreatment [ 18] which corre sponds to the dose range found to reduce sei zure activity [34] or NMDA-evoked brain pa thology (0.1-1 mg/kg) [35], but the dose-re sponse relationship in our study was quite the opposite to what we expected, with better effects with low (0.3-0.5 mg/kg) than high (0.75 mg/kg) doses of MK-801 ( fig.…”

Not All Models Are Created Equal: Animal Models to Study Hypoxic-Ischemic Encephalopathy of the Newborn

“…Other methods have been described, including intratracheal administration of meconium [10] and creation of experimental pneumothorax [11] . These strategies induce global hypoxia and ischemia, whereas other strategies specifically induce HIE in the animals by the combined use of carotid artery ligation and alveolar hypoxia or bleeding [12] . Because pathophysiologic mechanisms differ between strategies to induce asphyxia, the responses to interventions may vary.…”