The effects of general anesthetics on P2X7 and P2Y receptors in a rat microglial cell line.
BACKGROUND
Microglial cells play important roles in coordinating the inflammatory brain responses to hypoxia and trauma. Ionotropic P2X receptors and metabotropic P2Y receptors (P2YRs) expressed in microglia can be activated by extracellular adenosine triphosphate (ATP) derived from damaged cells or astrocytes, and participate in the signaling pathways evoked in brain insult. Although several inhaled and IV anesthetics produce neuroprotective effects through neuronal mechanisms, little is known about how general anesthetics modulate microglial responses in the pathological state. We examined the effects of various general anesthetics on purinergic responses in a rat microglial cell line.


METHODS
Currents were consistently activated by applications of ATP via a U-tube system under the whole-cell configuration. ATP-induced nondesensitizing currents observed after several applications of ATP exhibited characteristics of P2X7 receptors. The P2YRs-mediated mobilization of intracellular Ca2+ was measured using a Ca2+-sensitive fluorescent dye (fura-2).


RESULTS
Inhaled anesthetics (sevoflurane, isoflurane, and halothane) at doses three times as high as minimum alveolar concentrations had no effect on the P2X7Rs-mediated currents. IV anesthetics (ketamine, propofol, and thiopental) enhanced the P2X7Rs-mediated currents reversibly. The potencies for activation of P2X7Rs were not correlated with the octanol/buffer partition coefficients. Thiopental, at low concentrations, slightly inhibited the P2X7Rs-mediated currents, suggesting its dual actions on P2X7Rs. The P2YRs-mediated mobilization of intracellular Ca2+ was not affected by any of the general anesthetics tested.


CONCLUSIONS
Our results suggest that IV anesthetics, particularly thiopental and propofol, may modulate microglial functions through P2X7Rs in pathological conditions.
Nakanishi
Mika
M
Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan. m1383144@med.osaka-cu.ac.jp
Mori
Takashi
T
Nishikawa
Kiyonobu
K
Sawada
Makoto
M
Kuno
Miyuki
M
Asada
Akira
A
D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D017628:Microglia / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7
D018681:Anesthetics, General; C546470:P2rx7 protein, rat; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7