Effect of Propofol and Sevoflurane on Vanishing White Matter Models

Background: The leukodystrophy vanishing white matter (VWM) most often has its onset in childhood and is characterized by chronic decline and additionally stress-provoked acute neurological deterioration. Anesthesia is a stressor that can trigger this acute decline. The commonly used inhalational anesthetic sevoflurane has been reported to activate the integrated stress response (ISR), whereas the intravenous anesthetic propofol has not. We aimed to assess the differential effects of these anesthetics in models of VWM. Methods: We investigated the molecular effects of sevoflurane and propofol on the ISR in a murine neural cell line and in cultured astrocytes from patients with VWM and control subjects with immunostainings for prototypic ISR marker activating transcription factor 4 (ATF4). We determined the effects of these anesthetics on clinical signs and expression of ISR mRNAs in VWM and wild-type mice. Results: In the murine cell line, sevoflurane increased ATF4 accumulation compared with its vehicle (+157%); in contrast, propofol's vehicle without (−22%) and with (−23%) propofol decreased tunicamycin-increased levels of ATF4 to similar degree. Sevoflurane activated the ISR in astrocytes from control subjects (+17-33%) but not from patients with VWM (+1-2%). Propofol and its vehicle did not impact the ISR in astrocytes. The anesthetics did not have prolonged effects on motor skills in VWM mice but had small differential effects on ISR mRNA levels, consistently higher with sevoflurane than with propofol. Conclusions: We observed differential effects of the anesthetics in cultured neural cells and on expression levels of ISR markers in VWM mice, but not on clinical signs in VWM mice.