Search

Background: The mechanisms by which volatile anaesthetics such as isoflurane alter neuronal function are poorly understood, in particular their presynaptic mechanisms. Presynaptic voltage-gated sodium channels (Nav) have been implicated as a target for anaesthetic inhibition of neurotransmitter release. We hypothesize that state-dependent interactions of isoflurane with Nav lead to increased inhibition of Na+ current (INa) during periods of high-frequency neuronal activity. Methods: The electrophysiological effects of isoflurane, at concentrations equivalent to those used clinically, were measured on recombinant brain-type Nav1.2 expressed in ND7/23 neuroblastoma cells and on endogenous Nav in isolated rat neurohypophysial nerve terminals. Rate constants determined from experiments on the recombinant channel were used in a simple model of Nav gating. Results: At resting membrane potentials, isoflurane depressed peak INa and shifted steady-state inactivation in a hyperpolarizing direction. After membrane depolarization, isoflurane accelerated entry (ǀcontrol=0.36 [0.03] ms compared with ǀisoflurane=0.33 [0.05] ms, P<0.05) and slowed recovery (Tcontrol=6.9 [1.1]mscompared with ǀisoflurane=9.0 [1.9] ms, P<0.005) from apparent fast inactivation, resulting in enhanced depression of INa, during high-frequency stimulation of both recombinant and endogenous nerve terminal Nav. A simple model of Nav gating involving stabilisation of fast inactivation, accounts for this novel form of activity-dependent block. Conclusions: Isoflurane stabilises the fast-inactivated state of neuronal Nav leading to greater depression of INa during high-frequency stimulation, consistent with enhanced inhibition of fast firing neurones. [ABSTRACT FROM AUTHOR]

Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches. [ABSTRACT FROM AUTHOR]