Central relaxin-3 receptor (RXFP3) activation increases ERK phosphorylation in septal cholinergic neurons and impairs spatial working memory.

The medial septum/diagonal band (MS/DB) is a relay region connecting the hypothalamus and brainstem with the hippocampus, and both the MS/DB and dorsal/ventral hippocampus receive strong topographic GABA/peptidergic projections from the nucleus incertus of the pontine tegmentum. The neuropeptide relaxin-3, released by these neurons, is the cognate ligand for a Gi/o-protein-coupled receptor, RXFP3, which is highly expressed within the MS/DB, and both cholinergic and GABAergic neurons in this region of rat brain receive relaxin-3 positive terminals/boutons. Comprehensive in vitro studies have demonstrated that the cell signaling pathways altered by RXFP3 stimulation, include inhibition of forskolin-activated cAMP levels and activation of ERK phosphorylation. In this study we investigated whether intracerebroventricular (icv) injection of RXFP3-A2, a selective relaxin-3 receptor agonist, altered ERK phosphorylation levels in the MS/DB of adult male rats. We subsequently assessed the neurochemical phenotype of phosphorylated (p) ERK-positive neurons in MS/DB after icv RXFP3-A2 administration by dual-label immunostaining for pERK and neuronal markers for cholinergic and GABAergic neurons. Central RXFP3-A2 injection significantly increased levels of pERK immunoreactivity (IR) in MS/DB at 20 and 90 min post-injection, compared to vehicle and naive levels. In addition, RXFP3-A2 increased the number of cells expressing pERK-IR in the MS/DB at 90 (but not 20) min post-injection in cholinergic (but not GABAergic) neurons, which also expressed putative RXFP3-IR. Moreover, icv injection of RXFP3-A2 impaired alternation in a delayed spontaneous T-maze test of spatial working memory. The presence of RXFP3-like IR and the RXFP3-related activation of the MAPK/ERK pathway in MS/DB cholinergic neurons identifies them as a key target of ascending relaxin-3 projections with implications for the acute and chronic modulation of cholinergic neuron activity and function by relaxin-3/RXFP3 signaling.

The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation.

BACKGROUND: Western diet and lifestyle are associated with overweight, obesity, and type 2 diabetes, which, in turn, are correlated with neuroinflammation processes. Exercise and a healthy diet are important in the prevention of these disorders. However, molecules inhibiting neuroinflammation might also be efficacious in the prevention and/or treatment of neurological disorders of inflammatory etiology. The abscisic acid (ABA) is a phytohormone involved in hydric-stress responses. This compound is not only found in plants but also in other organisms, including mammals. In rodents, ABA can play a beneficial role in the regulation of peripheral immune response and insulin action. Thus, we hypothesized that chronic ABA administration might exert a protective effect in a model of neuroinflammation induced by high-fat diet (HFD). METHODS: Male Wistar rats were fed with standard diet or HFD with or without ABA in the drinking water for 12 weeks. Glucose tolerance test and behavioral paradigms were performed to evaluate the peripheral and central effects of treatments. One-Way ANOVA was performed analyzed statistical differences between groups. RESULTS: The HFD induced insulin resistance peripherally and increased the levels of proinflammatory markers in in the brain. We observed that ABA restored glucose tolerance in HFD-fed rats, as expected. In addition, chronic ABA treatment rescued cognitive performance in these animals, while not affecting control diet fed animals. Moreover, it counteracted the changes induced by HFD in the hypothalamus; microglia activations and TNFα mRNA levels. CONCLUSION: These results suggest that ABA might become a new therapeutic molecule improving the neuroinflammatory status and insulin resistance.