Osthole-Mediated Inhibition of Neurotoxicity Induced by Ropivacaine via Amplification of the Cyclic Adenosine Monophosphate Signaling Pathway

Abstract

Background Ropivacaine is widely used for clinical anesthesia and postoperative analgesia. However, the neurotoxicity induced by ropivacaine in a concentration- and duration-dependent manner, and it is difficult to prevent neurotoxicity. Osthole inhibits phosphodiesterase-4 activity by binding to its catalytic site to prevent cAMP hydrolysis. The aim of this present study is to explore the precise molecular mechanism of osthole-mediated inhibition of neurotoxicity induced by ropivacaine. Methods: SH-SY5Y cell viability and apoptosis were measured in different concentration and duration. Protein concentration was determined in each signaling pathway. The molecular mechanism of osthole-mediated inhibition of ropivacaine-caused neurotoxicity was evaluated. Results The study demonstrated that osthole inhibits SH-SY5Y cells neurotoxicity in a duration- and concentration-dependent manner. Moreover, ropivacaine significantly increased the expression of caspase-3 by promoting the phosphorylation of p38. Osthole-induced upregulation of cAMP activated cAMP-dependent signaling pathway, sequentially leading to elevated cyclic nucleotide response element-binding protein levels, which inhibits P38-dependent signaling and decreases apoptosis of SH-SY5Y. Conclusions This study display the evidence confirmed the molecular mechanism by which osthole amplification of cAMP-dependent signaling pathway, and overexpression of cyclic nucleotide response element-binding protein inhibits P38-dependent signaling and decreases ropivacaine-induced SH-SY5Y apoptosis.

Dexmedetomidine pretreatment alleviates ropivacaine-induced neurotoxicity via the miR-10b-5p/BDNF axis

“…As a key enzyme of anaerobic metabolism, LDH released from degenerated neurons can reflect the degree of nerve injury [ 40 ]. Accumulating studies have confirmed that neurotoxicity induced by local anesthetics is related to apoptosis [ 36 , 41 , 42 ]. Local anesthetics induce the activation of apoptotic neuronal cell death and finally determine the degree of nerve injury [ 43 ].…”

“…SH-SY5Y cells have been commonly used for the establishment of a cell model of ropivacaine-induced neurotoxicity [34]. The concentrations of ropivacaine and DEX used in this study were determined according to the previous literature reports [35][36][37]. Specifically, HT22 and SH-SY5Y cells were subjected to ropivacaine insult (0.5 mM, 1 mM, 2.5 mM, and 5 mM) for reproducing its damage characteristics.…”