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 α2-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 μM 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. Dexmedetomidine 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 μm vs. 1028 ± 213 μm, 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.


CONCLUSIONS
These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects.
Inserm, U676, Paris, France, Université Paris 7, Paris, France. degosv@gmail.com
Vincent
V
Degos
Tifenn Le
TL
Charpentier
Vibol
V
Chhor
Olivier
O
Brissaud
Sophie
S
Lebon
Leslie
L
Schwendimann
Nathalie
N
Bednareck
Sandrine
S
Passemard
Jean
J
Mantz
Pierre
P
Gressens
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D020927:Dexmedetomidine / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007051:Ibotenic Acid / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D010766:Phosphorylation; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D014158:Transcription, Genetic / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D006993:Hypnotics and Sedatives; D018696:Neuroprotective Agents; D007051:Ibotenic Acid; D012313:RNA; D020927:Dexmedetomidine