Identifying Potential Biomarkers, Mechanisms and Protective Strategies for General Anesthetic‐Induced Neurotoxicity in the Developing Nonhuman Primate

Abstract

It has been reported that commonly used general anesthetics such as sevoflurane induce neurotoxicity in developing brains. However, there has been limited research evaluating whether and how anesthetic agents affect bio‐lipids, the most abundant components of the brain other than water. Thus, assessing lipid profiles from blood samples may assist in the early detection of general anesthesia‐induced neurotoxic effects.Postnatalday (PND) 5 or 6 monkeys were randomly assigned to control (room‐air; n=4) and sevoflurane‐exposed(n=4) groups. Sevoflurane was delivered using an agent‐specific vaporizer for 9 hours at a clinically‐relevant concentration of 2.5%. Blood samples were collected at 0, 2, 4, 8 and 9 hours during exposure from both the control and sevoflurane‐exposed groups. Lipid extractions and analyses were performed using a mass spectrometer. Four hours after completion of anesthetic exposures front alcortical tissue was collected for histochemical and Western blot analyses. In addition, to evaluate potential protective strategies monkey infants were exposed to sevoflurane in the presence or absence of acetyl‐L‐carnitine(mitochondrial stabilizer), and microPET scanning using [18F]‐FEPPA was carried out to repeatedly visualize and quantify aspects of neurotoxicity.Serumlipidomic analyses demonstrated that the levels of critical lipid components including acylcarnitines, phosphatidylcholines and phosphatidylethanolamines were significantly decreased during prolongedexposure to sevoflurane. In contrast, the amounts of triglyceride and 4‐hydroxynonenal were increased to abnormally high levels in sevoflurane‐exposed monkeys. Consistently, histochemical staining and Western blot analyses of Bax protein revealed increased neuronal apoptotic damage after sevoflurane exposure. Co‐administration of acetyl‐L‐carnitine effectively blocked the neural damage (increased [18F]‐FEPPA signal)‐induced by prolonged sevoflurane exposure.These data suggest that prolonged exposure of neonatal monkeys to a clinically‐relevant concentration of sevoflurane resulted in significant changes in lipidmetabolism and subsequently, neuronal apoptotic damage. Monitoring specificlipid changes may provide insights into the molecular mechanism(s) underlying generalanesthetic‐induced neurotoxicity and serve as sensitive biomarkers for the early detection of anesthetic‐induced neuronal damage. Acetyl‐L‐carnitine may act to preserve cellular membrane integrity and play critical roles in mitochondrial oxidation of long‐chain fatty acids, and thus protect neurons from sevoflurane induced damage.Support or Funding InformationSupported by NCTR/FDAThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.