Title

 

Authors

E. Landucci¹, E.Gerace¹, T. Scartabelli¹, L. Filippi², G. la Marca², R. Guerrini² &  D. Pellegrini-Giampietro¹

1 Dept. of Preclinical and Clinical Pharmacology, University of Florence, Italy

2 Neonatal Intensive Care Unit, Dept. of Critical Care Medicine, “A. Meyer” University Children’s Hospital, Florence, Italy

 

Abstract

Perinatal hypoxia-ischemia is one of the most common risk factors for neonatal mortality and neurodevelopmental disability. With the recent introduction of hypothermia as a therapy for hypoxic-ischemic encephalopathy (HIE), there is hope for protection of neonatal brain after insult. Unfortunately, hypothermia alone does not provide complete protection and does not stimulate the repair mechanisms for an optimal neurodevelopmental outcome. Perinatal hypoxia is mediated, at least in part,  by abnormal glutamatergic transmission. In this study we tested the efficacy of hypothermia combined with memantine, a putative ideal non-competitive NMDA receptor blocker, and with topiramate an inhibitor of glutamate receptors (including kainate and AMPA) in in vitro and in vivo models of perinatal brain hypoxia-ischemia. For the in vitro experiments, we used rat organotypic hippocampal slices exposed to either oxygen-glucose deprivation (OGD) (Pellegrini-Giampietro et al., 1999) or to kainic acid (Nvue et al., 2004). When present in the incubation medium, memantine (1-30 µM) and topiramate (0.1-10 µM) significantly attenuated CA1 damage induced by 30 min of OGD. Our results show a synergic neuroprotective effect of memantine and topiramate in association with mild  hypothermia (32 or 35 °C). Hypothermia (32°C), but not memantine or topiramate alone or in combination, also attenuated the CA3 injury induced by kainate (5 µM for 24 h) in hippocampal slices. For the in vivo experiments, we used rat pups (7 days)  subjected to permanent left common carotid artery occlusion followed by 110-120 min of hypoxia (Vannucci et al., 2005). We observed a diffuse left brain injury and we tested the potential therapeutic intervention of memantine, topiramate, hypothermia alone or in combination. Seven days after HIE, we also performed a behavioral test (vibrissae stimulation) and rats were sacrificed for histological analysis of ischemic damage.
 
Pellegrini-Giampietro et al. (1999) Eur. J. Neurosci  11: 3637-3647
Nvue et al. (2004) Neurosci Lett 367: 365-8
Vannucci et al (2005)  Dev Neurosci 27: 81-6