Abstract
Background and aims: We have recently shown that Dextromethorphan is neuroprotective against excitotoxic and hyperoxic-induced brain injury. Beside its antagonistic effect on the NMDA [N-methyl-D-aspartate] receptor, DM also acts on sigma (σ) receptors. Sigma agonists have been shown to be neuroprotective in several adult animal models of brain injury. Neuroprotection by sigma agonists is accomplished by a variety of mechanisms like inhibition of presynaptic glutamate release and attenuation of postsynaptic glutamate-evoked Ca2+ influx. The selective σ1 receptor agonist Pre-084 [2-(4-Morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride] has been shown to be neuroprotective in in-vitro and in-vivo studies of adult brain injury. The aim of this study was to evaluate the effect of Pre-084 in NMDAR-mediated excitotoxic brain injury in newborn mice.
Methods: 5-day-old mice pups were injected intracranially with ibotenate, a glutamate analogon. 1 hour after injury pups were randomly injected intraperitoneally (i.p.) with i) 0.1μg/g body weight (bw) ii) 10μg/g bw iii) PBS as control. Enpoints were set at postnatal day 6 and 10 and processed for histological analysis.
Results: Pre-084 reduced NMDAR-mediated excitotoxic brain injury in grey matter if administered 1 hour after injury. The low dose of 0.1μg/g body weight was as effective as the high dose of 10μg/g bw compared to PBS injected control animals.
Conclusion: We show for the fist time a protective effect of the selective σ1 receptor agonist Pre-084 in an animal model of neonatal excitotoxic brain injury. Sigma agonists show a great protective potential and further analysis on the underlying mechanisms are ongoing.
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Groß, M., Medek, K., Urbanek, M. et al. 195 The Selective Sigma-1 Receptor Agonist Pre-084 Reduces Ndmar- Mediated Excitotoxic Brain Injury in Newborn Mice. Pediatr Res 68 (Suppl 1), 102 (2010). https://doi.org/10.1203/00006450-201011001-00195
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DOI: https://doi.org/10.1203/00006450-201011001-00195