NMDA Receptor Antagonism for Neuroprotection in a Canine Model of Hypothermic Circulatory Arrest

Katherine Giuliano, Kent A Stevens, Xun Zhou, Cecillia Lui, Alejandro Suarez-Pierre, Rishi Sharma, Mary Ann Wilson, Mary E. Blue, Juan C. Troncoso, Sujatha Kannan, Michael V. Johnston, Anjali Sharma, Rangaramanujam M. Kannan, Willian A. Baumgartner, Jennifer Lawton

Research output: Contribution to journalArticlepeer-review


Background: Hypothermic circulatory arrest (HCA) is associated with neurologic morbidity, in part mediated by activation of the N-methyl-D-aspartate glutamate receptor causing excitotoxicity and neuronal apoptosis. Using a canine model, we hypothesized that the N-methyl-D-aspartate receptor antagonist MK801 would provide neuroprotection and that MK801 conjugation to dendrimer nanoparticles would improve efficacy. Materials and methods: Male hound dogs were placed on cardiopulmonary bypass, cooled to 18°C, and underwent 90 min of HCA. Dendrimer conjugates (d-MK801) were prepared by covalently linking dendrimer surface OH groups to MK801. Six experimental groups received either saline (control), medium- (0.15 mg/kg) or high-dose (1.56 mg/kg) MK801, or low- (0.05 mg/kg), medium-, or high-dose d-MK801. At 24, 48, and 72 h after HCA, animals were scored by a standardized neurobehavioral paradigm (higher scores indicate increasing deficits). Cerebrospinal fluid was obtained at baseline, eight, 24, 48, and 72 h after HCA. At 72 h, brains were examined for histopathologic injury in a blinded manner (higher scores indicate more injury). Results: Neurobehavioral deficit scores were reduced by low-dose d-MK801 on postoperative day two (P < 0.05) and by medium-dose d-MK801 on postoperative day 3 (P = 0.05) compared with saline controls, but free drug had no effect. In contrast, high-dose free MK801 significantly improved histopathology scores compared with saline (P < 0.05) and altered biomarkers of injury in cerebrospinal fluid, with a significant reduction in phosphorylated neurofilament-H for high-dose MK801 versus saline (P < 0.05). Conclusions: Treatment with MK-801 demonstrated significant improvement in neurobehavioral and histopathology scores after HCA, although not consistently across doses and conjugates.

Original languageEnglish (US)
Pages (from-to)177-189
Number of pages13
JournalJournal of Surgical Research
StatePublished - Apr 2021


  • Brain histopathology
  • Dendrimer nanoparticles
  • Hypothermic circulatory arrest
  • NMDA receptor antagonism
  • Neuroprotection

ASJC Scopus subject areas

  • Surgery


Dive into the research topics of 'NMDA Receptor Antagonism for Neuroprotection in a Canine Model of Hypothermic Circulatory Arrest'. Together they form a unique fingerprint.

Cite this