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Neuroprotective effect of remifentanil on excitotoxic-induced brain damage in neonatal mice: an in vivo model

Presented at the Neonatal Society 2016 Summer Meeting.

Chollat C1,2, Tourrel F2,3, Lecointre M2, Ramdani Y2, Marret S1,2, Gonzalez B2, Dureuil B3, Jégou S2

1 ERI28 “NeoVasc”, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, IRIB, Rouen University, Rouen, France
2 Department of Neonatal Paediatrics and Intensive Care, Rouen University Hospital, Rouen, France
3 Department of Anesthetics and Intensive Care, Rouen University Hospital, Rouen, France

Background: Neuroprotection of premature newborns is a public health issue. The goal is, ultimately, to limit motor and cognitive impairments in the neonatal period. We have already shown that the morphinic remifentanil (Rf), used during perinatal care could be an interesting molecule to this end. Using an ex vivo model of brain slices from postnatal day 2 mice (P2), we previously showed that Rf exerts an anti-apoptotic activity.1 A model of neonatal brain injury by intracortical ibotenate injection was used to evaluate the in vivo effects of Rf treatment.

Methods: 3 groups of P2 mice were used: the Rf and NaCl groups received 3 ip injections of Rf (500 μg/kg over a 10-min period) or saline, respectively. Just after the last injection, ic injection of ibotenate (Ibo, 10 μg) was performed. A third group was composed of untreated mice. In situ labeling of cortical caspase activity was determined 5 hours after Ibo injection. The lesion size was assessed 5 days after the injection of Ibo. Finally, behavioral tests were done later between 3 and 12 days of life: righting and grasping reflex, negative geotaxis.

Results: Cortical caspase substrate consumption was significantly lower in Rf group (n = 11) vs NaCl group (n = 7) (62.45 vs 100 %). The size of the Ibo-induced lesion was significantly reduced in the Rf group (n = 32) vs NaCl group (n = 32) (226 +/- 47 vs 699 +/- 101 μm). Behavioral results showed that in the negative geotaxis test, the Rf-treated mice more rapidly rotated as compared to NaCl-treated mice (p <0.0001 for males and p = 0.011 for females). Performance of grasping reflex was better in the Rf group, only in males (p=0.0027). In both tests, Rftreated mice exhibited similar performance to untreated mice. No difference was found between Rf and NaCl groups for the negative righting reflex, treated pups turning less rapidly to a prone position than untreated mice.

Conclusion: The anti-apoptotic effect of Rf on the immature mouse brain previously shown using a model of organotypic cortical slices was found in a neonatal mice lesional model. This effect is associated with a neuroprotective action and preservation of some behavioral functions in the first 12 days of life.

Corresponding author: clement.chollat@gmail.com

References
1. Tourrel et al, Anesth Anal 2014.

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