exendin-(9-39) and geniposide

We recently discovered that the activation of the spinal glucagon-like peptide-1 receptors (GLP-1Rs) by the peptidic agonist exenatide produced antinociception in chronic pain. We suggested that the spinal GLP-1Rs are a potential target molecule for the management of chronic pain. This study evaluated the antinociceptive activities of geniposide, a presumed small molecule GLP-1R agonist. Geniposide produced concentration-dependent, complete protection against hydrogen peroxide-induced oxidative damage in PC12 and HEK293 cells expressing rat and human GLP-1Rs, but not in HEK293T cells that do not express GLP-1Rs. The orthosteric GLP-1R antagonist exendin(9-39) right-shifted the concentration-response curve of geniposide without changing the maximal protection, with identical pA2 values in both cell lines. Subcutaneous and oral geniposide dose-dependently blocked the formalin-induced tonic response but not the acute flinching response. Subcutaneous and oral geniposide had maximum inhibition of 72% and 68%, and ED50s of 13.1 and 52.7 mg/kg, respectively. Seven days of multidaily subcutaneous geniposide and exenatide injections did not induce antinociceptive tolerance. Intrathecal geniposide induced dose-dependent antinociception, which was completely prevented by spinal exendin(9-39), siRNA/GLP-1R and cyclic AMP/PKA pathway inhibitors. The geniposide iridoid analogs geniposidic acid, genipin methyl ether, 1,10-anhydrogenipin, loganin and catalpol effectively inhibited hydrogen peroxide-induced oxidative damage and formalin pain in an exendin(9-39)-reversible manner. Our results suggest that geniposide and its iridoid analogs produce antinociception during persistent pain by activating the spinal GLP-1Rs and that the iridoids represented by geniposide are orthosteric agonists of GLP-1Rs that function similarly in humans and rats and presumably act at the same binding site as exendin(9-39).

Topics: Analgesics; Animals; Central Nervous System Agents; Exenatide; Formaldehyde; Glucagon-Like Peptide-1 Receptor; HEK293 Cells; Heterocyclic Compounds, 3-Ring; Humans; Iridoid Glucosides; Iridoids; Male; Mice; Nociception; PC12 Cells; Peptide Fragments; Peptides; Rats; Rats, Wistar; Receptors, Glucagon; Spinal Cord; Venoms

β-Cell apoptosis is considered to be a major cause of loss of β cells in diabetes. Geniposide could prevent oxidative stress-induced neuron apoptosis, and improved glucose stimulated insulin secretion by activating glucagon-like peptide 1 receptor (GLP-1R) in INS-1 cells. Here we have investigated whether geniposide can exert a direct effect against pancreatic β-cell lipoapoptosis. The results indicated that pretreatment pancreatic INS-1 cells with geniposide for 7h attenuated palmitate-induced β-cell apoptosis and active caspase-3 expression, but this effect was disappeared at 18 h. Long-term incubation with palmitate decreased GLP-1R expression in INS-1 cells, and exendin (9-39), an antagonist for GLP-1R, inhibited the effect of geniposide on palmitate-induced apoptosis in INS-1 cells. Moreover, geniposide also improved the impairment of GLP-1R signaling through enhancing the phosphorylation of Akt and Foxo1, and increased the expression of PDX-1 in palmitate-treated INS-1 cells. These results suggest that geniposide inhibits early stage of lipotoxicity-induced β-cell apoptosis, and GLP-1R plays a critical role in geniposide counteracting the action of lipotoxicity in INS-1 pancreatic β cells.

Topics: Animals; Apoptosis; Caspase 3; Cell Line, Tumor; Drug Antagonism; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin-Secreting Cells; Iridoids; Palmitic Acid; Peptide Fragments; Rats; Receptors, Glucagon; Signal Transduction