Background: Preterm newborns are at high risk for neurologic deficits related to perinatal brain damage. Effective therapy is not yet available. As excitotoxicity – mainly mediated by glutamate on N-methyl-D-aspartate (NMDA) receptors – plays a crucial role in the process, the noncompetitive-NMDA receptor antagonist Dextromethorphan (DM) might reduce perinatal damage.

Aim of the study: We hypothesized that DM is neuroprotective in an animal model of periventricular leukomalacia (PVL). We asked:1) Which dosage of DM is the most effective in reducing brain damage? 2) Which time regimen is the most effective? 3) Does DM effect apoptosis in the brain?

Method: Ibotenic acid (Ibo), a glutamate-analogue, was injected into the right hemisphere (i.c.) of five day old mice to create white and gray matter (WM/GM) lesion mimicking PVL. After the insult animals were randomized into groups: a) Ibo i.c. b) Ibo i.c + once 1hr after injury intraperitoneal (i.p.) vehicle or, c) DM in a dosage of 1, d) 5 and e) 25µg/bwg. Then animals were randomized into groups a) Ibo i.c. + vehicle i.p., b) Ibo i.c. + 5µg/bwg DM i.p. once 1 hr before or, c) repetitively every 8hr starting 1 hr after injury d) combination of both. Study time-endpoint was at 120 hrs after injury and consisted of histological assessement of the lesion size (cresyl-violet staining) and counting apoptotic cells (activated Caspase-3 immunohistochemistry).

Results: Single application of 5 and 25 µg/bwg DM reduced lesion size by 31/26% in WM and 16/13% in GM (p<0,05, vs. control) but 1µg/bwg had no effect. 5µg/bwg DM before or after injury reduced lesion by 23/23% in WM and 12/10% in GM (p<0,05, vs. control) the combination of both reduced lesion size by 40% in WM and 23% in GM (p<0,001 vs. control and p<0,05 vs. other regimens) This reduction in lesion size was associated with a significant decrease of apoptotic cells in damaged hemisphere, whereas apoptosis in the non-injected hemisphere was unaffected.

Conclusion: DM reduces excitotoxic brain damage in newborn mice and decreases excitotoxicity-induced apoptosis with no effect on physiological occuring apoptosis.