Intravenous lipid emulsion modifies synaptic transmission in hippocampal CA1 pyramidal neurons after bupivacaine‐induced central nervous system toxicity

• Published in: Journal of neurochemistry 2020-07, Vol.154 (2), p.144-157
• Main Authors: Nie, Hao, Bai, Zhixia, Li, Zhenzhou, Yan, Li, Chen, Xue‐Xin
• Format: Article
• Language: English
• Subjects: Action potential; Anesthetics; Anesthetics, Local - toxicity; Animals; Apoptosis; Brain; Brain architecture; Brain slice preparation; Bupivacaine; Bupivacaine - toxicity; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - metabolism; Central nervous system; central nervous system toxicity; Fat Emulsions, Intravenous - pharmacology; hippocampal CA1 pyramidal neurons; Hippocampus; Hyperpolarization; Intravenous administration; Ion currents; Levels; lipid emulsion therapy; Lipids; Local anesthesia; local anesthetic systemic toxicity; Local anesthetics; Male; Nervous system; Neurons; Neurotoxicity Syndromes; Original; ORIGINAL ARTICLES; Pyramidal cells; Pyramidal Cells - drug effects; Pyramidal Cells - metabolism; Random Allocation; Rats; Rats, Sprague-Dawley; Synaptic transmission; Synaptic Transmission - drug effects; Toxicity; Western blotting; γ-Aminobutyric acid A receptors
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14924

Local anesthetics can cause severe toxicity when absorbed systemically. Rapid intravenous administration of lipid emulsion (LE) is the standard of care for severe local anesthetic systemic toxicity which can cause cardiovascular and central nervous system (CNS) injury. The biological mechanism by which LE alleviates CNS toxicity remains unknown and understudied. Previous research has suggested that local anesthetics cause an imbalance of excitatory and inhibitory transmission in the brain. Therefore, this study aimed to observe the effect of LE on glutamate‐ and GABA‐induced currents in CA1 pyramidal neurons after bupivacaine‐induced CNS toxicity. We further characterized post‐synaptic modifications in these cells to try to elucidate the mechanism by which LE mediates bupivacaine‐induced CNS toxicity. Sprague–Dawley rats received intravenous bupivacaine (1 mg kg−1 min−1) in either normal saline or LE (or LE without bupivacaine) for 5 min. An acute brain slice preparation and a combination of whole‐cell patch clamp techniques and whole‐cell recordings were used to characterize action potential properties, miniature excitatory, and inhibitory post‐synaptic currents, and post‐synaptic modifications of excitatory and inhibitory transmission in CA1 hippocampal pyramidal neurons. The expression level of GABAA receptors were assessed with western blotting, whereas H&E and TUNEL staining were used to assess cytoarchitecture and apoptosis levels respectively. Bupivacaine treatment significantly increased the number of observed action potentials, whereas significantly decreasing rheobase, the first interspike interval (ISI), and hyperpolarization‐activated cation currents (Ih) in CA1 pyramidal neurons. LE treatment significantly reduced the frequency of miniature inhibitory post‐synaptic currents and enhanced GABA‐induced paired pulse ratio with 50 ms interval stimulation in bupivacaine‐treated rats. Regulation of GABAA levels is a promising mechanism by which LE may ameliorate CNS toxicity after systemic absorption of bupivacaine. Bupivacaine (BPV) can affect the synthesis and release of glutamic acid and gamma‐aminobutyric acid in pre‐synaptic membrane. Changes the intensity of synaptic excitation or inhibition. This indirectly affects the electrical changes that occur when neurotransmitters bind to the post‐synaptic membrane. Including action potential (AP); miniature excitatory/inhibitory post‐synaptic currents (mEPSCs/mIPSCs); evoked excitatory post‐synaptic cu