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

Abstract

A need for new therapeutic approaches are necessary for dementia conditions and memory deficits of different origins, such as Alzheimer's disease. There is complex pathophysiological mechanisms involved, affecting adult hippocampal neurogenesis, in which neuropeptides and its neurogenesis regulation seem to participate. Neuropeptide Y(NPY) Y1 receptor (Y1R) and galanin (GAL) receptor 2 (GALR2) interact in brain regions responsible for learning and memory processes, emphasizing the hippocampus. Moreover, a significant challenge for treatments involving peptide drugs is bypassing the blood-brain barrier. The current study assesses the sustained memory performance induced by GALR2 and NPYY1R agonists intranasal coadministration and their neurochemical hippocampal correlates. Memory retrieval was conducted in the object-in-place task together with in situ proximity ligation assay (PLA) to manifest the formation of GALR2/Y1R heteroreceptor complexes and their dynamics under the different treatments. We evaluated cell proliferation through a 5-Bromo-2’-deoxyuridine (BrdU) expression study within the dentate gyrus of the dorsal hippocampus. The GalR2 agonist M1145 was demonstrated to act with the Y1R agonist to improve memory retrieval at 24 hours in the object-in-place task. Our data show that the intranasal administration is a feasible technique for directly delivering Galanin or Neuropeptide Y compounds into CNS. Moreover, we observed the ability of the co-agonist treatment to enhance the cell proliferation in the DG of the dorsal hippocampus through 5- Bromo-2’-deoxyuridine (BrdU) expression analysis at 24 hours. The understanding of the cellular mechanisms was achieved by analyzing the GALR2/Y1R heteroreceptor complexes upon agonist coactivation of their two types of receptor protomers in Doublecortin-expressing neuroblasts. Our results may provide the basis for developing heterobivalent agonist pharmacophores, targeting GALR2-Y1R heterocomplexes. It involves especially the neuronal precursor cells of the dentate gyrus in the dorsal hippocampus for the novel treatment of neurodegenerative pathologies as in the Alzheimer’s disease.

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

“…Following intranasal delivery of GALR2 and Y1R agonists we observed an increased cell proliferation in the ventral DG of the hippocampus by using the PCNA. In agreement, we have recently observed the ability of the coagonist intranasal infusion to enhance the cell proliferation in the DG of the dorsal hippocampus at 24 h (Borroto-Escuela et al, 2022). Previous work showed that icv infusion of GAL and the Y1R agonist-induced proliferation by using 5-bromo-2-deoxyuridine on the ventral hippocampus (Borroto-Escuela et al, 2021).…”

“…The doses indicated are based on previously published protocols (Borroto-Escuela et al, 2022;Serova et al, 2017).…”

“…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).…”

Synergistic effects of the galanin analog 810–2 with the antiseizure medication levetiracetam in rodent seizure models

“…For example, 810–2 has a short half‐life 28 and has not yet been optimized for oral administration. However, intranasal delivery of galanin analogs 19,69 has been shown to facilitate blood–brain barrier penetration, reduce food intake, and improve memory. Intranasal formulation and delivery of LEV 70 also suggests the potential for this route of administration as part of a combinatorial treatment strategy.…”

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery

“…The results of clinical trials are inconsistent, and it is likely that high doses are required to achieve a therapeutic effect, however, further investigation is necessary to make a meaningful conclusion [ 119 ]. Similarly, intranasal neuropeptide Y and galanin receptor agonists improved performance in memory retrieval tasks and increased cell proliferation in the dorsal hippocampus of rats [ 120 ].…”