Dexmedetomidine Alleviates LPS-Induced Neuronal Dysfunction by Modulating the AKT/GSK-3β/CRMP-2 Pathway in Hippocampal Neurons

Abstract

Objective Dexmedetomidine, an α2-adrenergic receptor agonist, mitigates cognitive dysfunction in elderly patients after surgery with general anesthesia. However, the underlying mechanism by which dexmedetomidine reduces cognitive dysfunction remains to be fully elucidated. The aim of this study was to investigate the effects of dexmedetomidine on lipopolysaccharide (LPS)-induced neuronal dysfunction in cultured hippocampal neurons. Methods LPS, in the presence and absence of dexmedetomidine, was applied to cultured hippocampal neurons to mimic post-surgical inflammation. Neuronal morphology, including neurite outgrowth and synaptic transmission, was observed, and miniature excitatory postsynaptic currents were recorded by electrophysiological patch-clamp. Results LPS significantly impaired neurite outgrowth in hippocampal neurons in a concentration- and time-dependent manner, which was reversed by dexmedetomidine treatment. Electrophysiological patch-clamp results showed that LPS induced synaptic transmission dysfunction, which was restored after dexmedetomidine addition. Furthermore, Western blotting assays showed that LPS suppressed the AKT/GSK-3β/CRMP-2 signaling pathway and dexmedetomidine countered the inhibitory effect of LPS by re-activating this pathway. Conclusion In general, dexmedetomidine protected against the effects of LPS-induced hippocampal neuron damage, including neurite outgrowth and synaptic transmission. Overall, dexmedetomidine modulated the AKT/GSK-3β/CRMP-2 signaling pathway to alleviate LPS-induced neurological dysfunction.

Dexmedetomidine Mitigates Microglial Activation Associated with Postoperative Cognitive Dysfunction by Modulating the MicroRNA-103a-3p/VAMP1 Axis

“…Earlier work revealed a role for dexmedetomidine in LPS-induced neuronal dysfunction [ 24 ]; however, the mechanism underlying microglia activation requires further elucidation. In LPS-exposed BV-2 cells treated with dexmedetomidine, the α 2 adrenoceptor agonist significantly suppressed LPS-induced VAMP1-upregulation (Figures 4(a) and 4(b) ).…”

“…Lysates extracted from BV-2 microglial cells or tissues were resolved on 10% SDS-polyacrylamide gels and transferred to polyvinylidene fluoride (PVDF) membranes [ 24 ]. The membranes were blocked with 5% milk and then incubated with recombinant anti-VAMP1 rabbit monoclonal antibody (ab151712, Abcam, Cambridge, UK) diluted 1 : 1000, or anti-GAPDH mouse monoclonal antibody (ab8245, Abcam) diluted 1 : 2000, at 4°C overnight.…”

“…Dexmedetomidine, a highly selective α 2-adrenergic receptor agonist, protects the CNS, heart, liver, and other organs by attenuating the inflammatory response [ 22 ]. Dexmedetomidine is neuroprotective in animal models of spinal cord and ischemic brain injury [ 23 ] and ameliorates LPS-induced neuronal dysfunction by modulating the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt)/glycogen synthase kinase-3 β (GSK-3 β )/collapsin response mediator protein 2 (CRMP-2) [ 24 ] pathways. Furthermore, dexmedetomidine suppresses LPS-induced microglial activation and inflammation [ 25 ].…”

The impact of CRMP4 SUMOylation on the Cav1.2 interaction, neurite outgrowth and thermal pain sensitivity

“…The procedure was performed as previously reported [27]. Briefly, cell lysates were separated by 10% SDS-PAGE and transferred onto a PVDF membrane (Millipore, Sigma, Burlington, MA, USA).…”

Identification of circRNA-miRNA-mRNA networks to explore the molecular mechanism and immune regulation of postoperative neurocognitive disorder

“…The global cost of dementia was estimated to be $818 billion in 2015 [6]. PND leads to delayed recovery, prolonged hospitalization, increased medical costs, enhanced complications, and even loss of self-care ability, resulting in a series of medical, social, and economic problems [7]. Several studies have explored the possible mechanism of PND, and neuroinflammation [8], neuronal apoptosis [9], autophagy disorders [10], and synaptic plasticity [11] have been reported.…”