Galanin and neuropeptide Y interactions elicit antidepressant activity linked to neuronal precursor cells of the dentate gyrus in the ventral hippocampus

Abstract

A need for new antidepressants is necessary since traditional antidepressants have several flaws. Neuropeptide Y(NPY) Y1 receptor (NPYY1R) and galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the hippocampus. The current study assesses the antidepressant effects induced by GALR2 and NPYY1R coactivation, together with the evaluation of cell proliferation through 5‐Bromo‐2'‐deoxyuridine expression within the dentate gyrus of the ventral hippocampus (vDG). We employed in situ proximity ligation assay to manifest GALR2/NPYY1R heteroreceptor complexes. Additionally, the expression pattern of GALR2 and the activation of the extracellular‐regulated kinases (ERK) pathway after GALR2 and NPYY1R costimulation in cell cultures were examined. GALR2 and NPYY1R coactivation resulted in sustained antidepressant behaviors in the FST after 24 h, linked to increased cell proliferation in the vDG. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was observed in vDG, on doublecortin‐expressing neuroblasts. Recruitment of the GALR2 expression to the plasma membrane was observed upon the coactivation of GALR2 and NPYY1R in cell cultures, presumably associated to the enhanced effects on the activation of ERK pathway. GALR2 may promote the GALR2/NPYY1R heteroreceptor complexes formation in the ventral hippocampus. It may induce a transformation of cell proliferation toward a neuronal lineage by enhancement of ERK pathway. Thus, it may give the mechanism for the antidepressant behavior observed. These results may provide the basis for the development of heterobivalent agonist pharmacophores, targeting GALR2/NPYY1R heteromers, especially in the neuronal precursor cells of the dentate gyrus in the ventral hippocampus for the novel treatment of depression.

Intranasal Delivery of Galanin 2 and Neuropeptide Y1 Agonists Enhanced Spatial Memory Performance and Neuronal Precursor Cells Proliferation in the Dorsal Hippocampus in Rats

“…Verification of GALR2 contribution was also established while the GALR2 antagonist M871 blocked the boosted response observed, as previously described ( Narvaez et al, 2015 ; Narvaez et al, 2016 ; Narvaez et al, 2018 ; Borroto-Escuela et al, 2021 ). Furthermore, neither M1145 and Y1R agonist nor their coadministration has shown locomotor alterations; thus, behavioural effects detected were independent of the motor actions, as described ( Narvaez et al, 2015 ; Narvaez et al, 2016 ; Narvaez et al, 2018 ).…”

“…Interestingly, enhanced spatial learning in ageing rodents was recently demonstrated by genetically boosting neurogenesis in the dorsal hippocampal DG ( Berdugo-Vega et al, 2020 ). With this approach, we observed the ability of the co-agonist treatment to enhance the cell proliferation in the DG of the dorsal hippocampus throughout 5-Bromo-2′-deoxyuridine (BrdU) expression analysis at 24 h. We have recently detected a rise of cell proliferation in the ventral hippocampus observed through BrdU analysis linked to antidepressant-like events ( Borroto-Escuela et al, 2021 ). In agreement, the molecule P7C3, known to have neuroprotective actions, increased the neuronal cell proliferation associated with improved spatial learning and memory effects in neurodegenerative rodent models ( Jiang et al, 2016 ; Loris et al, 2017 ).…”

“…Animals were allocated arbitrarily into five experimental groups: 1) Control: distilled water; 2) M1145- treated group (132 µg); 3) Y1R-treated group receiving the Y1R agonist [Leu 31 , Pro 34 ] NPY (132 µg); 4) M1145 + Y1R: group administered with both substances; 5) M1145 + Y1R + M871: group treated with M1145, [Leu 31 , Pro 34 ] NPY and the GALR2 antagonist (M871; 132 µg) (N = 4 in each group). The BrdU procedure ( Pilar-Cuellar et al, 2012 ; Abrial et al, 2014 ; Borroto-Escuela et al, 2021 ) is based on previously published procedures.…”

“…For positive control, a parallel analysis of the 5-HTR1A-5HTR2A isoreceptor complexes was completed as previously published ( Borroto-Escuela et al, 2017 ). In situ PLA image achievement and data evaluation were made as previously described ( Narvaez et al, 2020 ; Borroto-Escuela et al, 2021 ).…”

“…Recently, a facilitatory GAL/Y1R interaction was exposed, concerning the formation of GALR2/Y1R heteroreceptor complexes in the dentate gyrus of the ventral hippocampus. Moreover, GALR2 stimulation enhanced Y1R agonist-mediated antidepressant activities in the forced swimming test ( Borroto-Escuela et al, 2021 ).…”