GLP-1R Activation Ameliorate Novel-object Recognition Function via Hippocampal AMPK/NF-κB Signaling Pathway in Neuropathic Pain Mice

Abstract

Background: Growing evidences indicate that neuropathic pain is frequently accompanied with cognitive impairments, which aggravate the decrease in the quality of life of chronic pain patients. Furthermore, it has been shown that the activation of Glucagon-like-peptide-1receptor (GLP-1R) improved memory deficit in multiple diseases such as Alzheimer’s disease (AD), stroke and so on. However, whether activating GLP-1R could improve memory impairment induced by neuropathic pain and the mechanism by which this improvement would occur remain unclear. Methods: The spared nerve injury (SNI) model was established as a kind of neuropathic pain. And novel-object recognition memory (hippocampus-dependent memory) was tested by the novel object recognition test (NORT).The expression levels of GLP-1,GLP-1R,adenosine monophosphate-activated protein kinase (AMPK),p-AMPKThr172, nuclear factor κ B p65 (NF-κB p65), interleukin-1β p17(IL-1β p17),and the synaptic associated proteins were tested in the murine hippocampus with memory deficits caused by neuropathic pain. Then, exenatide acetate (Ex-4, a GLP-1R agonist), exendin(9-39)(Ex(9-39),a GLP-1R antagonist) and Compound C dihydrochloride ( CC, an AMPK inhibitor) were used to test the effects of activating GLP-1R in mice with neuropathic pain.Results: First, we uncovered that neuropathic pain could inhibit GLP-1/GLP-R axis, disturb inflammatory signaling pathway, increase the expression of IL-1β and downregulate the synaptic associated proteins (postsynaptic density protein 95(PSD95) and Arc). Subsequently, we reported that Ex-4 treatment could improve recognition memory impairment and increase the ratio of p-AMPKThr172/AMPK, decrease the expression of NF-κB p65 and IL-1β p17, upregulate the levels of PSD95 and Arc. Moreover, we uncovered that Ex(9-39) and CC treatment could abrogate the neuroprotection of Ex-4 in mice with memory impairment induced by neuropathic pain.Conclusions: The results indicated that the activation of GLP-1R could improve recognition memory impairment caused by neuropathic pain via activating AMPK signaling pathway, then, which could inhibit NF-κB activating and its downstream IL-1β expression, upregulate the levels of PSD95 and Arc proteins.