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J Thorac Cardiovasc Surg 2010;139:489-493
© 2010 The American Association for Thoracic Surgery

Perioperative Management

Ibuprofen for neuroprotection after cerebral ischemia

^a Children's National Heart Institute, Children's National Medical Center, Washington, DC
^b UMR-CNRS 6185, Université Caen, Caen, France

Presented at the 16th Annual Meeting of the Asian Society for Cardiovascular and Thoracic Surgery, March 15, 2008, Singapore.

Received for publication July 21, 2008; revisions received April 23, 2009; accepted for publication May 18, 2009.

^_* Address for reprints: Richard A. Jonas, MD, Children's National Heart Institute, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010. (Email: rjonas{at}cnmc.org).

Objective: Ibuprofen has been shown to reduce cerebral ischemic injury, such as may occur after deep hypothermic circulatory arrest. We investigated whether ibuprofen has direct protective effects against excitotoxic neuronal injury, as may be seen after cerebral ischemia, by using a cell culture model.

Methods: Mixed cortical cultures containing neuronal and glial cells were prepared from fetal mice at 13 to 15 days gestation, plated on a layer of confluent astrocytes from 1- to 3-day-old postnatal pups. Near-pure neuronal cultures containing less than 5% astrocytes were obtained from mice of the same gestational stage. Slowly triggered excitotoxic injury was induced at 37°C by 24-hour exposure to 12.5 µmol/L N-methyl-D-aspartate or 50 µmol/L kainate. Neuronal death was quantified by release of lactate dehydrogenase from damaged cells. Data were analyzed using 1-way analysis of variance with Tukey post hoc multiple comparisons.

Results: In mixed cultures, ibuprofen concentrations of 25 µg/mL, 50 µg/mL, and 100 µg/mL all significantly reduced N-methyl-D-aspartate–induced neuronal cell death from 74.5% to 56.1%, 38.7%, and 12.3%, respectively, revealing a strong dose response (P < .001). In near-pure cultures, ibuprofen at a concentration of 25 µg/mL failed to protect neurons, indicating that the neuroprotective effects of ibuprofen require interaction with glial cells. Furthermore, ibuprofen at 100 µg/mL was not protective against neuronal cell death induced by kainate exitotoxicity in near-pure culture but was effective in mixed cultures.

Conclusion: Ibuprofen provides neuroprotection through glial cells against excitotoxic neuronal injury caused by glutamatergic excitotoxicity after cerebral ischemia as demonstrated by reduced neuronal cell death in mixed cell cultures. Further studies are needed to evaluate the potential of ibuprofen to reduce neurologic injury in patients experiencing an hypoxic/ischemic insult.