Repeated lidocaine exposure induces synaptic and cognitive impairment in aged mice by activating microglia and neurotoxic A1 astrocytes.

In the perioperative setting, the administration of intravenous lidocaine is widespread. This study investigates the effects of varying frequencies of intravenous lidocaine on cognitive function in mice of differing ages. Young adult and aged mice received systemic lidocaine either once or three times. Our findings indicated that repeated exposure to systemic lidocaine in aged mice resulted in cognitive impairment, accompanied by neuronal apoptosis and synaptic loss in the hippocampus. Additionally, repeated lidocaine exposure activated microglia and neurotoxic A1 astrocytes in aged mice. Notably, the adverse effects were significantly diminished when aged mice were treated with dehydroxymethylepoxyquinomicin (DHMEQ), a specific NF-κB inhibitor. Furthermore, depleting microglia with PLX5622 effectively prevented the activation of A1 astrocytes and synaptic loss following lidocaine exposure. This study provides evidence linking age and exposure frequency to cognitive impairment due to systemic lidocaine administration, correlating with the activation of microglia and neurotoxic A1 astrocytes.