Sitagliptin improves functional recovery via GLP‐1R‐induced anti‐apoptosis and facilitation of axonal regeneration after spinal cord injury

Abstract

Axon growth and neuronal apoptosis are considered to be crucial therapeutic targets against spinal cord injury (SCI). Growing evidences have reported stimulation of glucagon‐like peptide‐1 (GLP‐1)/GLP‐1 receptor (GLP‐1R) signalling axis provides neuroprotection in experimental models of neurodegeneration disease. Endogenous GLP‐1 is rapidly degraded by dipeptidyl peptidase‐IV (DPP4), resulting in blocking of GLP‐1/GLP1R signalling process. Sitagliptin, a highly selective inhibitor of DPP4, has approved to have beneficial effects on diseases in which neurons damaged. However, the roles and the underlying mechanisms of sitagliptin in SCI repairing remain unclear. In this study, we used a rat model of SCI and PC12 cells/primary cortical neurons to explore the mechanism of sitagliptin underlying SCI recovery. We discovered the expression of GLP‐1R decreased in the SCI model. Administration of sitagliptin significantly increased GLP‐1R protein level, alleviated neuronal apoptosis, enhanced axon regeneration and improved functional recovery following SCI. Nevertheless, treatment with exendin9‐39, a GLP‐1R inhibitor, remarkably reversed the protective effect of sitagliptin. Additionally, we detected the AMPK/PGC‐1α signalling pathway was activated by sitagliptin stimulating GLP‐1R. Taken together, sitagliptin may be a potential agent for axon regrowth and locomotor functional repair via GLP‐1R‐induced AMPK/ PGC‐1α signalling pathway after SCI.

Teneligliptin Exerts Antinociceptive Effects in Rat Model of Partial Sciatic Nerve Transection Induced Neuropathic Pain

“…Our results demonstrated that TEN displayed great potential in alleviating NP in PSNT rats through a GLP-1R independent mechanism. Though several reports have shown the neuroprotective effects of TEN by the upregulation of GLP-1R in neurodegenerative diseases, our findings show that TEN can also induce antinociception and neuroprotection through GLP-1R independent mechanisms [29,[50][51][52][53][54].…”

“…Exendin-4, a peptide agonist of GLP-1 attenuated pain-induced cognitive impairment through the alleviation of neuroinflammation in NP rats [ 28 ]. In addition, DPP-4i like sitagliptin and GLP-1 analog liraglutide are shown to induce axonal regrowth and locomotor functional repair through the restoration of spinal GLP-1R levels in SCI rats [ 29 , 30 ].…”

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

“…AMPK is a critical sensor of energy status, which regulates cellular energy homeostasis [28]. Several studies have shown that activating AMPK could ameliorate in ammation by inhibiting the activation of NF-κB [13,14,29,30].Furthermore, it has been reported that AMPK could be activated as a downstream of GLP-1R,when GLP-1R is activated [10][11][12]31]. Stimulating GLP-1R using sitagliptin could facilitate axonal regeneration and locomotor functional repair after spinal cord injury via GLP-1R induced AMPK/PGC-1α signaling pathway activation [12].…”

“…Several studies have shown that activating AMPK could ameliorate in ammation by inhibiting the activation of NF-κB [13,14,29,30].Furthermore, it has been reported that AMPK could be activated as a downstream of GLP-1R,when GLP-1R is activated [10][11][12]31]. Stimulating GLP-1R using sitagliptin could facilitate axonal regeneration and locomotor functional repair after spinal cord injury via GLP-1R induced AMPK/PGC-1α signaling pathway activation [12]. A certain study has demonstrated that GLP-1 may suppress hepatic fat accumulation and in ammatory response induced by nutrients via the activation of the AMPK pathway [31].In our study, we demonstrated that AMPK was suppressed; however, NF-κB was hyperactive in mice with memory de cits caused by neuropathic pain.…”

“…It has been reported that AMPK, as a downstream of GLP-1R, can be activated when activating GLP-1R [10][11][12].Furthermore, the activation of AMPK can inhibit the downstream protein p65 NF-κB, which is involved in controlling neuroin ammation [13,14]. Additionally, activation of the NF-κB could promote the secretion of multiple pro-in ammatory cytokines including IL-1β [14,15], which contribute to neuropathic pain-induced memory impairment [16,17], and IL-1β p17 is a mature fragment of IL-1β.In addition, the activation of GLP-1R can attenuate the increased levels of IL-1β in the brain [8,18].…”