Neuroprotective Effects of Dexmedetomidine against Glutamate Agonist-induced Neuronal Cell Death Are Related to Increased Astrocyte Brain-derived Neurotrophic Factor Expression

Background: Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of a alpha(2)-adrenergic receptors, also provides neuroprotection against glutamate-induced damage. Because adrenergic receptor agonists can modulate BDNF expression, our goal was to examine whether dexmedetomidine's neuroprotective effects are mediated by BDNF modulation in mouse perinatal brain injury. Methods: The protective effects against glutamate-induced injury of BDNF and dexmedetomidine alone or in combination with either a neutralizing BDNF antibody or an inhibitor of the extracellular signal-regulated kinase pathway (PD098059) were compared in perinatal ibotenate-induced cortical lesions (n = 10-20 pups/groups) and in mouse neuronal cultures (300 mu(M) of ibotenate for 6 h). The effect of dexmedetomidine on BDNF expression was examined in vivo and in vitro with cortical neuronal and astrocyte isolated cultures. Results: Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dex-medetomidine enhanced Bdnf4 and Bdnf5 transcription and BDNF protein cortical expression in vivo. Dexmedetomidine also enhanced Bdnf4 and Bdnf5 transcription and increased BDNF media concentration in isolated astrocyte cultures but not in neuronal cultures. Dexmedetomidine's protective effect was inhibited with BDNF antibody (mean lesion size +/- SD: 577 +/- 148 mu m vs. 1028 +/- 213 mu m, n = 14-20, P < 0.001) and PD098059 in vivo but not in isolated neuron cultures. Finally, PD098059 inhibited the increased release of BDNF induced by dexmedetomidine in astrocyte cultures. Conclusion: These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects.