Propofol induce daño neuronal en ratones en desarrollo al inhibir la transcripción de EGR4 y regular la expresión de...

Propofol, a widely used intravenous anesthetic, has raised concerns regarding its potential neurotoxic effects on the developing brain. This study aimed to investigate the specific molecular mechanisms underlying propofol-induced neuronal damage during early development. Postnatal day 7 C57BL/6 J mice received a single intraperitoneal injection of propofol (50, 100, or 200 mg/kg) and hippocampal tissues were harvested 12 h post-exposure. Primary hippocampal neuronal cultures from mice embryos were exposed to propofol for 24 h. Genetic manipulations, including EGR4 and NPAS4 overexpression via plasmid transfection (in vitro) and adenovirus injection (in vivo), as well as NPAS4 knockdown using siRNA, were employed. Assessments included histopathology, apoptosis, cell viability, gene/protein expression, and transcriptional regulation. Propofol administration induced dose-dependent hippocampal neuronal injury in neonatal mice. Both in vitro (primary neurons) and in vivo (hippocampal tissue), ectopic overexpression of EGR4 via genetic manipulation significantly attenuated propofol-induced neurotoxicity. Mechanistically, EGR4 was found to directly bind to the NPAS4 promoter and positively regulate its transcription. Crucially, the anti-apoptotic effect of EGR4 overexpression was abolished upon NPAS4 knockdown. Our findings reveal a novel EGR4/NPAS4 transcriptional cascade through which propofol exerts its neurotoxic effects in the developing brain. Propofol downregulates EGR4 expression, leading to reduced NPAS4 transcription and subsequent neuronal apoptosis. While this pathway represents one potential mechanism of propofol-induced developmental neurotoxicity, it identifies EGR4 and NPAS4 as potential targets for therapeutic strategies aimed at mitigating anesthetic-related neuronal injury in the vulnerable developing brain.