GLP‑1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK/NF‑κB signaling pathways in streptozotocin‑induced diabetic rats

Abstract

The present study aimed to investigate the mechanism of glucagon‑like peptide‑1 receptor (GLP‑1R) agonists in the progression of diabetic peripheral neuropathy (DPN) in streptozotocin (STZ)‑induced diabetic rats, through inflammatory signaling pathways. The DPN rat model was generated by intraperitoneal injection of STZ and then treated with the GLP‑1R agonist liraglutide or saline for 8 weeks. These animals were randomly divided into 4 groups (10 rats in each): The normal control + saline group, the normal control + liraglutide group, the diabetic + saline (DM) group and the diabetic + liraglutide (DML) group. The nerve conduction velocity (NCV) in the sciatic nerves of the rats was monitored over a period of 8 weeks. Peripheral serum was obtained for the measurement of blood glucose, tumor necrosis factor‑α (TNF‑α), interleukin‑6 (IL‑6) and IL‑1β level. The protein levels of phosphorylated (p‑) and total extracellular signal‑regulated kinase, c‑Jun NH2‑terminal kinases, p38 mitogen‑activated protein kinases (MAPK), and nuclear and cytoplasmic nuclear factor‑κB (NF‑κB) were measured through western blot analysis. Sciatic nerve mRNA expression levels of proinflammatory chemokines (TNF‑α, IL‑6 and IL‑1β), chemokines [monocyte chemoattractant protein‑1 (MCP‑1)], adhesion molecules [intercellular adhesion molecule 1 (ICAM‑1)], neurotrophic factors [neuritin, nerve growth factor (NGF) and neuron‑specific enolase (NSE)] and NADPH oxidase 4 (NOX4) were evaluated by reverse transcription-quantitative polymerase chain reaction. Subsequent to 8 weeks of treatment with liraglutide, the density of myelin nerve fibers was partially restored in the DML group. The delayed motor NCV and sensory NCV in the DML group were improved. The IOD value of NOX4 staining in the DML group (24.43±9.01) was reduced compared with that in the DM group (56.60±6.91). The levels of TNF‑α, IL‑1β and IL‑6 in the peripheral serum of the DML group were significantly suppressed compared with those of the DM group. It was also observed that the mRNA expression levels of TNF‑α, IL‑6, IL‑1β, MCP‑1, ICAM‑1 and NOX4 in the sciatic nerve were attenuated in the DML group. The mRNA expression of neuritin and NGF was significantly increased in the DML group compared with that of the DM group; NSE was reduced in the sciatic nerves of the DML group compared with that of the DM group. Additionally, the protein expression of p‑p38 MAPK and NF‑κB in the DML group was significantly suppressed. These data demonstrated that GLP‑1R agonists may prevent nerve dysfunction in the sciatic nerves of diabetic rats via p38 MAPK/NF‑κB signaling pathways independent of glycemic control. GLP‑1R agonists may be a useful therapeutic strategy for slowing the progression of DPN.

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

“…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 ].…”

Gene Expression Profiling of the Sciatic Nerve in Streptozotocin-Induced Diabetic Rats with Peripheral Neuropathy

“…Similarly, Feldman et al found that nerve growth factor-induced mechanical allodynia in the db/db mouse was mediated by the phosphorylation of p38 and the upregulation of multiple inflammatory mediators in lumbar dorsal root ganglia [19]. Several studies have demonstrated that inhibitors targeting the p38/MAPK pathway ameliorated inflammatory processes and neurological deficits in experimental DPN [20][21][22]. While it has been indicated that the regulatory function of p38 kinases on inflammatory processes is mainly through p38α (and probably β), the role of p38γ and p38δ in inflammation is unknown [17].…”

Semaglutide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain containing 3 inflammasome in pentylenetetrazole‑kindled mice

“…Previous studies have shown that GLP-1 agonists inhibit NLRP3 inflammasome activation through sirtuin1 signaling to alleviate cardiovascular impairment (44,45). Another study found that GLP-1 agonists alleviated inflammation and attenuated peripheral nerve injury via the p38 MAPK/NF-κB pathway (46). A previous study also indicated that ibuprofen has antiepileptic and neuroprotective effects through the cyclooxygenase-2/NLRP3 pathway in PTZ-kindled mice (18).…”