galanin-like-peptide and Disease-Models--Animal

Alarin is a newly identified member of the galanin family of neuropeptides. Until now, research on alarin is limited compared with other members of the galanin family. Unearthing the new biological effects of alarin and its unidentified receptor(s) interests us. We previously showed that alarin has an effect on depression-like behaviors, although the underlying mechanisms are not fully clarified. The present study verified the antidepressant-like effects of alarin using the unpredictable chronic mild stresses (UCMS) paradigm, and explored the mechanism that underlies antidepressant-like effects of alarin in mice. Previous research has shown that TrkB receptor-mediated ERK and AKT signaling pathways participate in depression pathophysiology. Therefore, we aimed to explore whether alarin improved depression-like behaviors by increasing activity of ERK and AKT pathways mediated by TrkB. Results showed that alarin significantly reduced immobility time in the forced swim test and latency to feed in the novelty suppressed feeding test. In addition, decreased p-ERK/ERK and p-AKT/AKT levels in the prefrontal cortex, hippocampus, olfactory bulb, and hypothalamus induced by UCMS were reversed by intracerebroventricular injection of alarin. Results suggested that alarin increased p-ERK/ERK and p-AKT/AKT levels by acting on the TrkB receptor. To verify this hypothesis, mice were pretreated with the TrkB inhibitor K252a (or 0.1% dimethyl sulfoxide, intraperitoneally, 3 days), followed by intracerebroventricular injection of alarin. This resulted in an absence of antidepressant-like effects, as well as no activation of ERK and AKT signaling pathways. Results demonstrate that alarin may exert antidepressant-like effects by targeting TrkB receptor-mediated ERK and AKT signal systems, which could help to identify the alarin receptor.

Topics: Animals; Antidepressive Agents; Brain; Carbazoles; Cyclic AMP Response Element-Binding Protein; Depressive Disorder; Disease Models, Animal; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Galanin-Like Peptide; Indole Alkaloids; Male; Mice, Inbred C57BL; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, trkB; Signal Transduction; Stress, Psychological

Galanin-like peptide (GALP) is a novel peptide that has been isolated from the porcine hypothalamus. The expression of GALP mRNA is localized to the hypothalamic arcuate nucleus and is thought to be under the regulation of leptin. First, we confirmed by real-time PCR analysis that sc administration of leptin to Wistar rats under food-deprived conditions resulted in a 1.5-fold increase in hypothalamic GALP mRNA levels. Next, GALP mRNA levels were found to be reduced by 50% in 11-wk-old male Zucker obese rats compared with age-matched Zucker lean rats, whereas neuropeptide Y mRNA levels were increased by 55% and proopiomelanocortin mRNA levels were reduced by 53% in Zucker obese rats. Analysis using a two-site enzyme immunoassay revealed a lower level of hypothalamic GALP immunoreactivity in 11-wk-old Zucker obese rats (5.9 fmol/mg protein) than in age-matched Zucker lean rats (19.6 fmol/mg protein). Immunohistochemical studies demonstrated that Zucker obese rats (11 wk old) had a reduced number of GALP immunoreactivity-positive cells (29.4 cells/3 slices) in the arcuate nucleus compared with age-matched Zucker lean rats (115 cells/3 slices). Furthermore, Zucker obese rats showed increased sensitivity to intracerebroventricularly administered GALP compared with Zucker lean rats, in that a lower dose of GALP increased plasma LH levels in male Zucker obese rats, but not in male Zucker lean rats. In addition, a reduction in the level of hypothalamic GALP mRNA was found in db/db and ob/ob mice. The result supports the hypothesis that the hypothalamic GALP gene expression is controlled by leptin signals and suggests possible involvement of GALP in the reproductive abnormalities of the Zucker obese rat.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Galanin-Like Peptide; Gene Expression; Injections, Intraventricular; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Nerve Tissue Proteins; Neurons; Obesity; Rats; Rats, Wistar; Rats, Zucker; RNA, Messenger; Signal Transduction; Up-Regulation