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.