Authors: Jung S et al.
Journal: Anesthesiology, Accepted December 19, 2025. DOI: 10.1097/ALN.0000000000005910
Summary
This experimental laboratory study investigated the mechanism by which isoflurane disrupts neuronal calcium homeostasis, providing mechanistic insight into anesthetic-induced neurotoxicity. Using cultured mouse neurons (both wildtype and mitochondrial mutant), the investigators tested whether prolonged intracellular calcium elevation during anesthetic exposure is driven by impaired calcium removal rather than increased calcium influx.
Under baseline conditions, electrical stimulation produced a transient presynaptic calcium rise that rapidly returned to baseline. Isoflurane exposure dramatically prolonged calcium decay time, indicating defective calcium clearance. This impairment was closely linked to inhibition of mitochondrial complex I, resulting in reduced ATP availability at presynaptic terminals.
Restoration of intracellular ATP levels with high-glucose conditions normalized calcium clearance despite ongoing isoflurane exposure, directly implicating ATP depletion as the primary driver. Pharmacologic activation of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) similarly corrected delayed calcium removal, identifying SERCA failure as the key downstream mechanism.
Isoflurane exposure was also associated with reduced mitochondrial dye uptake and increased cleaved caspase expression, signaling early mitochondrial injury and apoptotic activation. Comparable findings in mitochondrial mutant neurons exposed to lower, equipotent concentrations of isoflurane reinforced the central role of mitochondrial vulnerability in this process.
Key Points
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Isoflurane markedly impairs neuronal calcium clearance after synaptic activation.
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The defect is due to inhibition of mitochondrial ATP production, not increased calcium entry.
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SERCA-dependent calcium removal is the primary ATP-dependent pathway affected.
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Restoring ATP levels or pharmacologically activating SERCA rescues calcium handling.
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Calcium dysregulation is associated with early markers of mitochondrial damage and apoptosis.
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These findings provide a mechanistic link between volatile anesthetic exposure and anesthetic-induced neurotoxicity.
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