Abstract
Background: General anaesthetics are essential for paediatric surgery but have been associated with neuronal injury and long-term cognitive deficits, thereby raising concerns over neurodevelopmental safety. However, the molecular mechanisms underlying anaesthetic-induced developmental neurotoxicity remain poorly understood.
Methods: Human cerebral organoids derived from induced pluripotent stem cells were exposed to propofol (1-6 h; single or repeated exposures). In parallel, serum samples were collected from paediatric patients (age: <4 yr; n=10 per group) undergoing short (<1 h) or prolonged (>3 h) anaesthetic procedures. Organoid pathology and mitochondrial function were assessed using chemical assays, electron microscopy, and immunoblotting. Genome-wide profiling of 18 855 coding RNAs (mRNAs) and 27 427 long noncoding RNAs (lncRNAs) was performed by microarray analysis.
Results: Propofol exposure increased apoptosis (1.9 [0.3] vs 1.0 [0.1]; P=0.0173) and autophagy (0.78 [0.12] vs 0.45 [0.09]; P=0.028) in organoids, and dysregulated 553 mRNAs and 792 lncRNAs linked to synaptic function, mitochondrial activity, and inflammation. ATP production (P=0.045), and expression of CKMT1B (P=0.002) and synaptic markers PSD95 and c-Fos were reduced. Serum from children exposed to prolonged anaesthesia showed elevated neuronal injury markers and 33 overlapping dysregulated RNAs (21 mRNAs, 12 lncRNAs), including CKMT1B. Bioinformatics revealed enrichment of these dysregulated lncRNA-mRNA networks in pathways related to cell injury, neurodevelopment, and cognition.
Conclusions: This study establishes a human-relevant model of anaesthetic-induced developmental neurotoxicity by integrating human organoids with clinical serum profiling. Propofol exposure led to mitochondrial dysfunction and disruption of coding RNA and lncRNA networks involved in neuronal development and injury. Concordant gene signatures (e.g. CKMT1B) across models highlight their potential as translational biomarkers and therapeutic targets.
Tarun Pant, et al,
British Journal of Anaesthesia October 2025