|DEXTROMETHORPHAN`IS (DM) NEUROPROTECTIVE AGAINST SENSITIZED NMDA-RECPETOR MEDIATED PERINATAL BRAIN DAMAGE IN NEWBORN MICE|
|Gergely Sárközy1,2 –
Maria Auer1 – Elke Griesmaier1 – Georg Simbruner1 – Martina Urbanek1 –
1Department of Paediatrics, Medical University Innsbruck;
21st and 2nd Department of Paediatrics, Semmelweis University;
Background: We have previously shown that the N-methyl-D-aspartate receptor (NMDAR) antagonist DM is neuroprotective against excitotoxic brain damage of newborn mice. As DM has also anti-inflammatory effect, might be also beneficial in inflammation sensitized brain injury, which is a key pathogenic factor in brain damage in preterm infants
Studyquestion. We hypothesized that DM decreases also inflammation mediated exacerbation of brain injury in newborn mice.
Methods: We used a newborn mice model of excitotoxic brain damage, in which the glutamate-analogue Ibotenat (Ibo) to activate NMDAR or S-Bromowillardiine (SBW) to activate DM-independent ά-amino-3-hydroxy-5-methyl-isoxazol-4-proprionic acid receptors (AMPA /Kainat) were injected into one hemisphere of 5 days old (P5) mice to mimic periventricular leukomalacia. In our experiment, firs,t pups were randomized in i) Interleukin-1β (IL) or ii) E.coli Lipopolisaccharide (LPS) pretreated groups to create proinflammation or iii) control group. Then animals were randomized into two groups as intracranially i) Ibo or ii) SBW injected. Finally, after setting brain injury, animals were treated with repetitive DM 5µg/bwg or sham. As endpoints we determined intracranial lesion size, apoptosis, microglial cell activation 24 hours after setting the lesion (P6).
Results: IL and LPS significantly increased lesion size in both Ibo and SBW injured group, versus control. DM reduced significantly NMDAR but not AMPA/KainateR mediated brain damage in inflammatory non-presensitised group. Furthermore, DM blocked LPS and IL induced increase in both Ibo and SBW injected group.
Conlusion: We conclude that additively to its NMDAR blocking effect, DM is neuroprotective also via its anti-inflammatory potential in excitotoxic brain damage of newborn mice.