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Lu, C. W.; Chen, I. Y.; Lin, T. Y.; Wang, S. J.
Far Eastern Memorial Hospital, Department of Anaesthesiology, Taipei, Taiwan, Republic of China
Background and Goal of Study: Dexmedetomidine is a highly selective α2A‐adrenergic receptor agonist, which has been widely used for sedation in the intensive care unit and operating room. Dexmedetomidine has been found to be neuroprotective in recent studies and the exact mechanisms haven't been fully verified. Considering the fact that glutamate is the principle excitatory neurotransmitter in the brain and excessive glutamatergic synaptic transmission can cause neuronal excitotoxicity, we hypothesized that dexmedetomidine may exhibit its neuroprotective effect through inhibiting glutamate release
Materials and Methods: Isolated nerve terminals (synaptosomes) purified from Sprague‐Dawley rat cerebral cortex were used to examine the effect of dexmedetomidine on glutamate release evoked by 4‐aminopyridine (4‐AP). The attribution of different α2 receptor subtypes on the dexmedetomidinemediated glutamate release was also determined by different subtype antagonists. The effects of dexmedetomidine on the Synaptosomal membrane potential and Ca2+ influx were also examined by DiSC3(5) and Fura‐2, respectively. Finally, Western blotting was used to investigate the downstream signaling pathway.
Results and Discussion: Results showed that dexmedetomidine exhibited a dose‐dependent inhibition of 4‐AP‐evoked release of glutamate. The effect of dexmedetomidine on the evoked glutamate release was abolished by α2A adrenergic receptor antagonist, BRL44408, but was insensitive to α2B antagonist, ARC239. In addition, this inhibition was prevented by chelating the intrasynaptosomal Ca2+ ions and by the vesicular transporter inhibitor. Dexmedetomidine decreased depolarization‐induced increase in intrasynaptosomal Ca2+, whereas it did not alter the resting synaptosomal membrane potential or 4‐AP‐mediated depolarization. Moreover, the inhibitory effect of dexmedetomidine on evoked glutamate release was prevented by the mitogen‐activated protein kinase (MAPK) inhibitors PD98059 and U0126. Western blotting showed that dexmedetomidine significantly decreased the 4‐AP‐induced phosphorylation of MAPK, and this effect was blocked by PD98059.
Conclusion(s): Dexmedetomidine inhibits glutamate release from rat cortical synaptosomes through the suppression of presynaptic voltage‐dependent Ca2+ entry and MAPK signaling cascade. This may delineate the mechanism of neuroprotective effect provided by dexmedetomidine in neuropathological conditions associated with excessive glutamate release.
© 2011 European Society of Anaesthesiology
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