• Qiang Xiang, Lei Tan, Yilin Zhao, Jintao Wang, and Ailin Luo.
• Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
• Med. Hypotheses. 2008 Dec 1; 71 (6): 868-71.

AbstractIsoflurane is one of the most commonly used inhalation anesthetic in neonatal anaesthesia. It has been suggested that isoflurane can induce caspase activation and apoptosis when applied in a clinically relevant concentration in the developing brain. Recent researches have indicated that a clinically relevant isoflurane treatment may induce neurodegeneration and apoptosis by activating the endoplasmic reticulum (ER) membrane inositol 1,4,5-trisphosphate (IP(3)) receptor, producing excessive calcium release from ER to the cytoplasm and triggering apoptosis. Although the exact mechanism by which isoflurane induces apoptosis still needs further study, it is generally accepted that the increase of cytosolic free calcium levels is the major risk factor. Previous studies have found that during early postnatal life, activation of gamma-aminobutyric acid (GABA(A)) receptor reduces the voltage-dependent Mg(2+) block of N-methyl-d-aspartate (NMDA) channels in neurons and increases cytosolic calcium levels by potentiated the Ca(2+) influx through NMDA channels; while in the adult, it may enhance the voltage-dependent Mg(2+) block of NMDA channels and decrease the Ca(2+) influx through NMDA channels. Since isoflurane acts at the GABA(A) receptor in an agonistic manner, here we presume that isoflurane increases intracellular calcium in neonatal neurons not only by activating IP(3) receptors in the endoplasmic reticulum (ER) membrane, but also by activating the GABA(A) receptor and depolarizing the postsynaptic membrane enough to facilitate NMDA receptor-mediated Ca(2+) influx. Meanwhile, we hypothesized that ketamine, a widely used pediatric anesthetic, acts as a noncompetitive antagonist of the NMDA type of glutamate receptors, which may be the best partner for isoflurane in neonatal anesthesia for it may attenuate isoflurane-induced caspase activation and apoptosis in the neonatal neurons by inhibiting the isoflurane-induced elevation in cytosolic calcium not only by blocking the NMDA receptors, but also by suppressing inositol triphosphate formation in the cytoplasm.

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