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.
Background and Purpose: 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 GALR2 and Y1R agonists interaction
upon intranasal infusion in the ventral hippocampus. Experimental
approach: We studied their hippocampal proliferating actions using the
proliferating cell nuclear antigen (PCNA) and the expression of of the
brain-derived neurothrophic factor (BDNF). Moreover, we studied the
formation of Y1R-GALR2 heteroreceptor complexes and analyzed
morphological changes on hippocampal neuronal cells. Finally, the
functional outcome of the NPY and GAL interaction on the ventral
hippocampus was evaluated in the forced swimming test. Key Results: We
demonstrated that the intranasal infusion of GALR2 and the Y1R agonists
promotes cell proliferation in the DG 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. Conclusions & Implications: 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 mayor depression disorder or depressive-affecting
diseases.
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