GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant‐like effects involving BDNF actions

Abstract

Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID‐19 pandemic. Accumulating evidence for neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular‐, cellular‐, and behavioral‐specific levels. The purpose of the current work was to evaluate the proliferating role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expression of the brain‐derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R–GALR2 heteroreceptor complexes and analyzed morphological changes in hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes neuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R–GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant‐like effects after GALR2 and the Y1R agonists intranasal administration. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R–GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of MDD or depressive‐affecting diseases.

Long‐term enhancements in antidepressant efficacy and neurogenesis: Effects of intranasal co‐administration of neuropeptide Y 1 receptor (NPY1R) and galanin receptor 2 (GALR2) agonists in the ventral hippocampus

“…[50][51][52][53] However, this observation is particularly relevant considering speciesspecific differences in antidepressant responses between rats and mice, 75 as evidenced by studies on mice showing antidepressant-like effects of a spexin-based GALR2 agonist within 2-3 h. 76 The role of the GALR2 antagonist M871 in counteracting the enhanced response observed further substantiates the specific involvement of GALR2 and NPY1R in these effects. 41,43 Our also previous research indicating the involvement of the ventral hippocampus in the antidepressant effects of NPY in conditions like posttraumatic stress disorder 77 and the higher expression of NPY1R in the ventral compared to the dorsal hippocampus. 58 While the observed antidepressant-like effects of NPY1R and GALR2 agonist co-administration persisting for 3 weeks post-treatment represent a significant finding, extending the analysis beyond this timeframe presents logistical and ethical challenges.…”

“…This observation is in line with our previous reports on the short-term actions of these agonists in various brain regions, including the amygdala and hippocampus. [36][37][38]40,43 Additionally, the involvement of 5HT1A-FGFR1 heteroreceptor complexes in stimulating hippocampal plasticity linked to antidepressant-like actions further supports this mechanism. 78,79 The evaluation of NPY1R-GALR2 PLA numbers in the ventral hippocampus could serve as a unique biomarker for single-cell resolution, demonstrating drug target engagement with localized precision.…”

“…PCNA-labeled cells in the hippocampus were quantified using unbiased stereological microscopy. 38,39,43 Additional method details are provided in the supplementary material.…”

“…This cross-talk could explain the synergistic or antagonistic effects observed in experimental studies when both neuropeptides are administered simultaneously. [36][37][38][39][40][41][42] Our recent experimental studies have delved into these interactions, exploring how NPY1R and GALR2 agonists stimulate proliferation in ventral neuronal precursors in the dentate gyrus, demonstrating antidepressive-like actions within 24 h. 40,43 These insights could pave the way for novel therapeutic approaches in treating mental disorders.…”

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury

“…As shown in Figure A, a total of 152 genes were upregulated and 157 genes were downregulated in the Ri@EGCG-2 NP group compared with the SCI group. Remarkably, among the upregulated genes in the Ri@EGCG-2 NP group, there were numerous genes related to SCI repair including nerve regeneration, synaptic remodeling, and extracellular mechanism remodeling (Figure B), such as Galr2, Mospd4, Lilrb3a, Col22a1, Col2a1, etc. − Similarly, the significant enrichments in Gene Ontology (GO) biological processes (BP), molecular function (MF), and cellular component (CC) (Figure C, Figures S16 and S17) showed that the pathways related to stem cell proliferation, axon regeneration, neuron regeneration, synaptic remodeling, and extracellular matrix remodeling were significantly enriched in the Ri@EGCG-2 NPs group compared with the SCI group. − To confirm the results of RNA sequencing, sections and immunofluorescence staining were performed on the spinal cord tissue at the injury site. As shown in the immunofluorescence staining with DAPI and Nestin (to label neural stem cells (NSCs)) images in Figure D and quantitative analysis in Figure E, there was a small amount of Nestin-positive NSCs in SCI groups, and more noticeable Nestin-positive NSCs filled the injury site in the Ri@EGCG-2 NPs group.…”