The Janus Face of Isoflurane: A Dose–Age-Response Model of Cognitive Impact

Isoflurane remains a cornerstone of clinical anaesthesia, valued for its robust pharmacological profile. However, its long-term neurological impact, specifically its potential to trigger cognitive impairment, remains a subject of intense debate. As a highly lipophilic agent that readily penetrates the blood–brain barrier, isoflurane exerts complex modulatory effects on various neurotransmitter systems and signaling cascades. While traditional paradigms have predominantly focused on isoflurane-induced neurotoxicity, characterised by neuronal apoptosis, oxidative stress and neuroinflammation, emerging evidence reveals a more nuanced, “Janus-faced” reality. Intriguingly, exposure to low doses during specific developmental stages has been shown to enhance cognitive function and consolidate memory. This suggests that a unidimensional toxicity model fails to capture the drug’s full biological spectrum. In this review, we propose a “dose–age-effect” model, a novel two-dimensional framework designed to reconcile these divergent findings. By categorising isoflurane’s impact across distinct developmental and mature neurobiological stages, we systematically synthesise high-quality evidence ranging from molecular signaling to behavioural phenotypes. We also examine the underlying mechanistic landscape and evaluate potential intervention strategies. This integrated perspective advances our theoretical understanding of anaesthetic–brain interactions and provides a roadmap for optimising clinical protocols and mitigating the risk of adverse postoperative cognitive outcomes.