Galanin and Neuropeptide Y Interaction Enhances Proliferation of Granule Precursor Cells and Expression of Neuroprotective Factors in the Rat Hippocampus with Consequent Augmented Spatial Memory

Abstract

Dysregulation of hippocampal neurogenesis is linked to several neurodegenereative diseases, where boosting hippocampal neurogenesis in these patients emerges as a potential therapeutic approach. Accumulating evidence for a 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 role of the NPY and GAL interaction in the neurogenic actions on the dorsal hippocampus. We studied the Y1R agonist and GAL effects on: hippocampal cell proliferation through the proliferating cell nuclear antigen (PCNA), the expression of neuroprotective and anti-apoptotic factors, and the survival of neurons and neurite outgrowth on hippocampal neuronal cells. The functional outcome was evaluated in the object-in-place task. We demonstrated that the Y1R agonist and GAL promote cell proliferation and the induction of neuroprotective factors. These effects were mediated by the interaction of NPYY1 (Y1R) and GAL2 (GALR2) receptors, which mediate the increased survival and neurites’ outgrowth observed on neuronal hippocampal cells. These cellular effects are linked to the improved spatial-memory effects after the Y1R agonist and GAL co-injection at 24 h in the object-in-place task. Our results suggest the development of heterobivalent agonist pharmacophores, targeting Y1R–GALR2 heterocomplexes, therefore acting on the neuronal precursor cells of the DG in the dorsal hippocampus for the novel therapy of neurodegenerative cognitive-affecting diseases.

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

“…C-Fos-labeled cells were studied using the optical fractionator method in unbiased stereological microscopy (Olympus BX51 Microscope), as previously described (Borroto-Escuela et al, 2022;Mirchandani-Duque et al, 2022;Narváez et al, 2018) (see Supporting Information: Materials for details).…”

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System

“…The loss of stress resilience and the functional impairment of mitochondria have been linked to neuropsychiatric symptoms comorbidities of neurological diseases such as AD, PD, HD, ALS, FA, and Charcot–Marie–Tooth disease [ 166 , 167 , 168 ]. Preclinical animal research plays a major role in revealing the involvement of endogenous peptides, neurohormones, and metabolites including KYNs [ 169 , 170 , 171 , 172 , 173 , 174 , 175 ].…”

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

“…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.…”