Sevoflurane leads to learning and memory dysfunction via breaking the balance of tPA/PAI-1

Abstract

Exposure to general anesthesia in early childhood may lead to adverse effects on adolescent neurocognition. This study investigated the effects of multiple inhalations of sevoflurane on long-term learning and memory in developing rats, and explored the mechanistic role of the tissue plasminogen activator (tPA)/plasminogen activator inhibitor-1 (PAI-1) fibrinolysis system and its regulatory relationship with the brain derived neurotrophic factor (BDNF) by activation of tropomysin related kinase B (TrkB). After rats were inhaled with sevoflurane for 2 h/d for three days, the expression levels of tPA, PAI-1, BDNF, its precursor(proBDNF), TrkB and phosphorylation of TrkB (p-TrkB) were detected at different time points. After 28 d, Morris water maze was used to examine learning and memory function; Golgi staining was used to investigate synaptic plasticity and synaptic-related proteins, such as Synapsin I(SYN1), growth associated protein 43(GAP-43), and postsynaptic density protein 95(PSD-95). Rats were given exogenous tPA and an inhibitor of PAI-1, TM5275. The results showed multiple inhalation of sevoflurane led to learning and memory dysfunction, downregulated the expression of the synaptic-related proteins, decreased dendritic spine density in the hippocampus, increased the expression level of proBDNF and PAI-1, and reduced expression of BDNF, tPA, and p-TrkB. Interestingly, tPA or TM5275 partially reversed the learning and memory dysfunction and the reduction of synaptic plasticity induced by sevoflurane exposure. Furthermore, they blocked the upregulation of proBDNF and PAI-1 protein expression and increased the expression of BDNF, tPA, and p-TrkB. The protective effect of tPA or TM5275 on rats following multiple sevoflurane inhalation was blocked by a TrkB inhibitor. Multiple inhalation of sevoflurane in rats inhibited the cleavage of proBDNF by disrupting the balance of the tPA/PAI-1 fibrinolysis system. This blocked the activation of the downstream TrkB signaling pathway and reduced hippocampal synaptic plasticity, leading to long-term learning and memory dysfunction. Therefore, Sevoflurane exposure could lead to learning and memory dysfunction by inhibiting BDNF cleavage via breaking the balance of tPA/PAI-1.

Keywords: BDNF; Neurotoxicity; PAI-1; Sevoflurane; tPA.