Somatostatin and its receptors involvement in sevoflurane-induced neurotoxicity: a narrative review

As a widely used pediatric anesthetic, sevoflurane presents a paradoxical neurodevelopmental risk during vulnerable brain maturation periods. This review synthesizes emerging evidence on sevoflurane-induced developmental neurotoxicity, with a focus on somatostatin (SST)-SSTR4 signaling and its downstream effects on synaptic integrity. Key findings reveal that sevoflurane exposure disrupts excitatory-inhibitory balance by upregulating hippocampal SST expression, suppressing glutamatergic synaptic markers (vesicular glutamate transporter 1 (vGLUT1), PSD95), and impairing cAMP/PKA signaling—a pathway essential for AMPA receptor trafficking and synaptic plasticity. Mechanistically, SSTR4 activation exacerbates synaptic dysfunction through adenylate cyclase (AC) inhibition, reducing cAMP levels and diminishing AMPA receptor phosphorylation. Primate and rodent models corroborate these effects, linking SST-SSTR4 dysregulation to long-term cognitive deficits. Single-nucleus RNA sequencing in macaques further identifies altered synaptic development genes after sevoflurane exposure. While preclinical data suggest SSTR4 modulation as a therapeutic target, causal relationships between sevoflurane, SSTergic signaling, and synaptic pathology remain unconfirmed. This work underscores the urgency of refining pediatric anesthesia protocols and developing neuroprotective strategies targeting the SST-SSTR4-cAMP/PKA axis. Future research should prioritize spatiotemporal profiling of SST dynamics, validation of SSTR4-specific interventions, and translational studies using non-human primate models to bridge mechanistic insights with clinical outcomes.