The committe of the "Medizinischer Forschungsfonds Tirol" desided in their last conference in December 2008 to give a grant to the laboratory of neonatal neuroscience for the project: Dextromethorphan : an "old" drug to protect the newborn against brain injury? Dr. Elke Griesmaier and her team will use the grant to deepen the knowledge on the role of Dextromethorphan in the newborn brain and thus continue their previous work.

Background

Preterm neonates, especially those who are suffering from respiratory distress syndrome, often require supplementation of oxygen to improve systemic oxygenation. During the last years evidence has been rising that oxygen used at supra-physiological concentrations (hyperoxia) constitutes a neurotoxic factor and induces injury in the immature brain. Several lines of evidence also suggest a role of maternal and fetal infection and inflammation in the pathogenesis of preterm birth and subsequently neonatal brain lesions. Furthermore the developing white matter (WM) is highly susceptible to ischemic insults, due to the developmental aspects of blood supply in the preterm brain.The above mentioned major processes are thought to use certain molecular pathways which lead to excess oxidative stress, nitric oxide synthase upregulation, release of reactive oxygen species and inordinate release of excitatory amino acids.

Potential role of Dextromethorphan

A neuroprotective effect of N-Methyl-D-Aspartate (NMDA)-receptor blockers has been shown in animal models of hypoxic-ischemic and excitotoxic brain damage. But beside this neuroprotective effect, competitive NMDA-receptor blockers have significant adverse effects and act in a pro-apoptotic way that limits their use in the developing brain. That being the case, drugs with multipotent mechanisms of action are required which do not interfere with the subtly regulated development of the immature brain. Dextromethorphan (DM), a low-affinity non-competitive NMDAR antagonist with additional anti-inflammatory properties, might constitute such a drug, since the agent itself lacks pro-apoptotic effects and the activation of NMDA-receptors and inflammation play a crucial role in the pathogenesis of hyperoxia-induced brain injury.

Own work on Dextromethorphan

Our group has shown for the first time a neuroprotective effect of Dextromethorphan in an animal model of neonatal excitotoxic brain injury. In a pilot study we have also tested the effect of DM in a newborn rat model of hyperoxia in cooperation with the pulmonary research group, Medical University Innsbruck. We investigated the effect of DM on apoptosis. The results were promising, showing a decrease of apoptosis in DM treated animals after hyperoxia compared to PBS injected control animals. However this study had several limitations for our purposes as the primary focus of this study was the lung and not the brain.
Therefore we now adapted the model to the brain and with the grant from the MFF this promising study will be started immediately.