Background: Dexmedetomidine is a specific agonist of the α2A-adrenoceptor with sedative, analgesic, neuro-protective, and anti-delirious effects. At clinically relevant concentrations, it stimulates both inhibitory auto-receptors and post-junctional receptors found on astrocytes, but not on neurons. The stimulated pathway releases epidermal growth factor receptor (EGFR) agonist(s) that can act on all brain cell types. Dexmedetomidine's ability to improve treatment and prognosis in critically ill patients in the ICU is clinically relevant.
Methods: Dexmedetomidine's neuro-protectant mechanisms of action were tested during oxidative damage, using cultured astrocytes and the very vulnerable glutamatergic cerebellar granule neurons. Primary cultures of cerebellar granule neurons prepared from 7-day-old CD-1 mice were cultured for 8 days, and primary cultures of astrocytes from newborn CD-1 mice for 3 weeks until full maturation. Cell viability during extended incubation with and without H2O2 was tested by a methylthiazoletetrazolium (MTT) assay, and released heparin-binding epidermal growth factor (HB-EGF) in medium from astrocyte cultures measured by sandwich ELISA.
Results: Dexmedetomidine administration directly to H2O2-exposed neurons had no cyto-protective effect. Conditioned medium from astrocytes treated for 30-120 min with 50 nM dexmedetomidine increased neuronal survival by >50%, provided astrtocytic α2-adrenoceptors were not atipamezole-inhibited. Dexmedetomidine's protective effect was also prevented when neuronal treatment with astrocyte-conditioned medium took place in the presence of AG 1478, inhibiting neuronal EGF receptors.
Conclusion: At clinically relevant concentrations dexmedetomidine is neuro-protective against oxidative damage by stimulating astrocytic α2-adrenoceptors, causing release of HB-EGF. HB-EGF in turn activates neuronal EGF receptors. At these concentrations dexmedetomidine has no direct neuronal effect.
Keywords: Astrocyte, dexmedetomidine, EGF receptor, H2O2, neuron, transactivation