Enhancing Cognitive Functions and Neuronal Growth through NPY1R Agonist and Ketamine Co-Administration: Evidence for NPY1R-TrkB Heteroreceptor Complexes in Rats.

This study investigates the combined effects of the neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31-Pro34]NPY at a dose of 132 µg and Ketamine at 10 mg/Kg on cognitive functions and neuronal proliferation, against a backdrop where neurodegenerative diseases present an escalating challenge to global health systems. Utilizing male Sprague-Dawley rats in a physiological model, this research employed a single-dose administration of these compounds and assessed their impact 24 h after treatment on object-in-place memory tasks, alongside cellular proliferation within the dorsal hippocampus dentate gyrus. Methods such as the in situ proximity ligation assay and immunohistochemistry for proliferating a cell nuclear antigen (PCNA) and doublecortin (DCX) were utilized. The results demonstrated that co-administration significantly enhanced memory consolidation and increased neuronal proliferation, specifically neuroblasts, without affecting quiescent neural progenitors and astrocytes. These effects were mediated by the potential formation of NPY1R-TrkB heteroreceptor complexes, as suggested by receptor co-localization studies, although further investigation is required to conclusively prove this interaction. The findings also highlighted the pivotal role of brain-derived neurotrophic factor (BDNF) in mediating these effects. In conclusion, this study presents a promising avenue for enhancing cognitive functions and neuronal proliferation through the synergistic action of the NPY1R agonist and Ketamine, potentially via NPY1R-TrkB heteroreceptor complex formation, offering new insights into therapeutic strategies for neurodegenerative 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.

This study evaluates the sustained antidepressant-like effects and neurogenic potential of a 3-day intranasal co-administration regimen of galanin receptor 2 (GALR2) agonist M1145 and neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31, Pro34]NPY in the ventral hippocampus of adult rats, with outcomes analyzed 3 weeks post-treatment. Utilizing the forced swimming test (FST), we found that this co-administration significantly enhances antidepressant-like behaviors, an effect neutralized by the GALR2 antagonist M871, highlighting the synergistic potential of these neuropeptides in modulating mood-related behaviors. In situ proximity ligation assay (PLA) indicated a significant increase in GALR2/NPYY1R heteroreceptor complexes in the ventral hippocampal dentate gyrus, suggesting a molecular basis for the behavioral outcomes observed. Moreover, proliferating cell nuclear antigen (PCNA) immunolabeling revealed increased cell proliferation in the subgranular zone of the dentate gyrus, specifically in neuroblasts as evidenced by co-labeling with doublecortin (DCX), without affecting quiescent neural progenitors or astrocytes. The study also noted a significant uptick in the number of DCX-positive cells and alterations in dendritic morphology in the ventral hippocampus, indicative of enhanced neuronal differentiation and maturation. These morphological changes highlight the potential of these agonists to facilitate the functional integration of new neurons into existing neural circuits. By demonstrating the long-lasting effects of a brief, 3-day intranasal administration of GALR2 and NPY1R agonists, our findings contribute significantly to the understanding of neuropeptide-mediated neuroplasticity and herald novel therapeutic strategies for the treatment of depression and related mood disorders, emphasizing the therapeutic promise of targeting neurogenesis and neuronal maturation processes.

Neuropeptide Y receptor 1 and galanin receptor 2 (NPY1R-GALR2) interactions in the dentate gyrus and their relevance for neurogenesis and cognition.

Introduction: This study may unveil novel insights into the interactions between neuropeptide Y receptor 1 (NPY1R) and galanin receptor 2 (GALR2), in the dentate gyrus of the dorsal hippocampus, shedding light on their role in neurogenesis and cognitive functions. Existing literature highlights the potential of these interactions in enhancing learning and memory, yet detailed mechanisms remain underexplored. Methods: Utilizing intracerebroventricular injections of GALR2 and NPY1R agonists in Sprague-Dawley male rats, we examined neurogenesis via markers PCNA and DCX, and memory consolidation through the object-in-place task over a three-week period. Results: Significant increases in NPY1R-GALR2 co-localization and neuroblast proliferation were observed, alongside enhanced memory consolidation. These findings suggest a synergistic effect of NPY1R and GALR2 activation on cognitive functions. Discussion: Our findings may foster the development of novel heterobivalent or multitargeting drugs, affecting NPY1R-GALR2 interaction, and suggest a future pharmacogical strategy for improving learning and memory found in many brain diseases. Further research is encouraged to explore these mechanisms in pathological models.

Enhancement of neurogenesis and cognition through intranasal co-delivery of galanin receptor 2 (GALR2) and neuropeptide Y receptor 1 (NPY1R) agonists: a potential pharmacological strategy for cognitive dysfunctions.

BACKGROUND: Spatial memory deficits and reduced neuronal survival contribute to cognitive decline seen in the aging process. Current treatments are limited, emphasizing the need for innovative therapeutic strategies. This research explored the combined effects of intranasally co-administered galanin receptor 2 (GALR2) and neuropeptide Y1 receptor (NPY1R) agonists, recognized for their neural benefits, on spatial memory, neuronal survival, and differentiation in adult rats. After intranasal co-delivery of the GALR2 agonist M1145 and a NPY1R agonist to adult rats, spatial memory was tested with the object-in-place task 3 weeks later. We examined neuronal survival and differentiation by assessing BrdU-IR profiles and doublecortin (DCX) labeled cells, respectively. We also used the GALR2 antagonist M871 to confirm GALR2's crucial role in promoting cell growth. RESULTS: Co-administration improved spatial memory and increased the survival rate of mature neurons. The positive effect of GALR2 in cell proliferation was confirmed by the nullifying effects of its antagonist. The treatment boosted DCX-labeled newborn neurons and altered dendritic morphology, increasing cells with mature dendrites. CONCLUSIONS: Our results show that intranasal co-delivery of GALR2 and NPY1R agonists improves spatial memory, boosts neuronal survival, and influences neuronal differentiation in adult rats. The significant role of GALR2 is emphasized, suggesting new potential therapeutic strategies for cognitive decline.