Aprotinin confers neuroprotection by reducing excitotoxic cell death

Yusuke Iwata, Olivier Nicole, Toru Okamura, David Zurakowski, Richard A. Jonas
The Journal of Thoracic and Cardiovascular Surgery. 2008-03-01; 135(3): 573-578
DOI: 10.1016/j.jtcvs.2007.08.076

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1. J Thorac Cardiovasc Surg. 2008 Mar;135(3):573-8; discussion 578. doi:
10.1016/j.jtcvs.2007.08.076. Epub 2008 Jan 18.

Aprotinin confers neuroprotection by reducing excitotoxic cell death.

Iwata Y(1), Nicole O, Okamura T, Zurakowski D, Jonas RA.

Author information:
(1)Department of Cardiovascular Surgery, Children’s National Heart Institute,
Washington, DC 20010, USA.

OBJECTIVE: Aprotinin is used in cardiac surgery for its anti-inflammatory and
hemostatic benefits. Recent reports describe the neuroprotective effects of other
serine protease inhibitors via reduced excitotoxic cell death, a common pathway
causing cytotoxic edema induced in various neuropathologic conditions. The
purpose of this study was to investigate whether aprotinin directly protects
against glutamatergic excitotoxicity in cell cultures.
METHODS: Mixed cortical cultures containing neuronal and glial cells were
prepared from fetal mice at 13 to 15 days’ gestation and plated on a layer of
confluent astrocytes from 1- to 3-day-old postnatal pups. Near-pure neuronal
culture containing less than 5% astrocytes was obtained from the same gestational
stage and plated in multiwell vessels previously coated with poly-D-lysine and
laminin. Both cultures were used at 12 to 14 days in vitro. Slowly triggered
excitotoxicity was induced at 37 degrees C by 24-hour exposure to 12.5 microM
N-methyl-D-aspartate or 50 microM kainate. Neuronal death was quantified by
measuring the release of lactate dehydrogenase from damaged cells into the
bathing medium. Data were analyzed by analysis of variance with post hoc
Bonferroni comparisons.
RESULTS: Aprotinin at a clinically relevant concentration of 100 KIU/mL
significantly reduced N-methyl-D-aspartate-induced neuronal death in both pure
and mixed cultures (P < .001). Aprotinin also reduced neuronal death induced by
kainate from 36% to 23% in mixed cortical culture (P = .008) and from 40% to 27%
in near-pure culture (P = .015), indicating that the neuroprotective effects of
aprotinin are mediated directly through neurons.
CONCLUSION: Aprotinin provides direct neuroprotection against glutamatergic
excitotoxicity as demonstrated by reduced neuronal death in near-pure neuronal
cell culture. Additional studies are needed to evaluate the potential of
aprotinin to reduce neurologic injury in patients at high risk of cerebral
injury, including those undergoing circulatory arrest.

DOI: 10.1016/j.jtcvs.2007.08.076
PMID: 18329472 [Indexed for MEDLINE]

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