EVALUATING THE ANTIDEPRESSANT POTENTIAL OF A NEW BBB PERMEABLE RXFP3 AGONIST IN RODENTS

Relaxin-3 and its receptor RXFP3 (relaxin family peptide receptor 3) are expressed in the brain. This system regulates mood, stress and motivational drive. RXFP3 activation shows promising antidepressant-like effects. However, current RXFP3 agonists are unable to cross the blood-brain barrier (BBB), necessitating to develop BBB-permeable agonists. This project involves testing the ability of a newly developed BBB-permeable RXFP3 agonist to alter depression-relevant behaviours in rodents.
RXFP3 agonist was administrated once weekly to wildtype C57BL/6 mice (1.0 μmol/kg, subcutaneous) and Sprague-Dawley rats (32 nmol/kg, intranasal) versus saline control. Different behavioural paradigms were tested during the 1 hour after each administration, and transcriptome analysis was conducted on postmortem brains collected 90 min after a final injection.
RXFP3 agonist treatment increased food and water intake in rats, while no such effects were observed in mice, in-line with previously observed species differences in RXFP3-illicited feeding responses. Importantly, RXFP3 agonist treatment decreased anxiety-like behaviour (light/dark box) and increased arousal/motivational drive (open field test) in both species. RXFP3 agonist treatment did not alter behaviour in RXFP3 knockout mice, confirming that these effects in wildtypes were selectively mediated through RXFP3. Transcriptional profiling of rat hippocampus identified gene sets linked to memory and neurogenesis that were significantly influenced by RXFP3 agonist treatment.
Taken together this project validates the novel RXFP3 agonist as a BBB permeable compound suitable for future research. Furthermore, the ability of RXFP3 agonist treatment to reduce and anxiety and influence hippocampal neurogenesis further supports RXFP3 as a promising therapeutic target for the treatment of depression.