Propofol prevents peroxide-induced inhibition of glutamate transport in cultured astrocytes

Background: Glutamate transporters located in the plasma membrane of cerebr al astrocytes take up excitatory neurotransmitters from the synaptic cleft. In diseases characterized by oxidative stress, the extracellular glutamate concentration increases and contributes to neuronal death. The authors wan ted to determine whether propofol defends brain cells against oxidant-induc ed changes in their transport of glutamate. Methods: Primary cultures of rat cerebral astrocytes were exposed to tert-b utyl hydroperoxide (1 mM) to serve as an in vitro model of oxidative stress . Astrocytes were incubated with propofol for 2 h and tert-butyl hydroperox ide was added for the final hour. Alternatively, astrocytes were incubated with tert-butyl hydroperoxide for 30 min and then with propofol for another 30 mini, Control cells received drug vehicle rather than propofol. The rat e of uptake of glutamate, the efflux of the nonmetabolizable analog D-aspar tate, and the intracellular concentration of the endogenous antioxidant glu tathione were measured. Results: Tert-butyl hydroperoxide decreased the glutathione concentration a nd inhibited glutamate uptake but had a negligible effect on D-aspartate ef flux. At clinically relevant concentrations. propofol did not affect the gl utathione concentration bur did prevent the effect of tert-butyl hydroperox ide on glutamate transport. Furthermore, the addition of propofol after ter t-butyl hydroperoxide reversed the inhibition of glutamate uptake. Conclusions: Propofol prevents and reverses the inhibition of excitatory am ino acid uptake in astrocytes exposed to tert-butyl hydroperoxide, The abil ity of propofol to defend against peroxide-induced Inhibition of glutamate clearance riley prevent the pathologic increase in extracellular glutamate at synapses, and thus delay or pre-vent the onset of excitotoxic neuronal d eath.