The hemoglobin-derived peptide LVV-H7 attenuates select behavioral alterations in male spontaneously hypertensive rats.

LVV-H7 is a decapeptide derived from the β-hemoglobin chain, with its mRNA expressed in multiple brain regions implicated in the regulation of endocrine functions and behavior. LVV-H7 inhibits the insulin-regulated aminopeptidase (IRAP) catalytic actions on oxytocin (OT) and displays behavioral effects that rely on oxytocin receptors (OTR) in control rats. However, effects on hyperactive behavioral disorders such as those observed in spontaneously hypertensive rats (SHR) remained unknown to date. SHR and Wistar (WT) rats were injected (i.p.) with vehicle (NaCl 0.9%) LVV-H7 at doses of 0.1 or 10 mg/kg 30 min before assessing locomotion, exploration, anxiety- and depressive-like behaviors in open field (OF), elevated plus maze (EPM), and forced swim (FS) tests. Blood samples were taken to measure plasma OT levels. Hypothalamic samples were used to compare WT and SHR's expression of OTR protein. In silico, the primary structure of OT, OTR and IRAP was compared among WT, SHR and humans. SHR spent more time in the EPM open arms and exhibited greater grooming and crossing episodes, in addition to the augmented crossing and rearing episodes in the OF. In SHR but not in WT, LVV-H7 reduced the time spent in the EPM closed arms, the rearing episodes during EPM and OF tests, and the immobility time during FS. While LVV-H7 increased plasma OT levels in WT, the same treatment decreased circulating OT in SHR. Hypothalamic OTR protein levels did not differ between strains. Although either OT or OTR structures are identical between WT and SHR, in silico assays suggest that IRAP of SHR may display alterations on the trafficking region. In conclusion, LVV-H7 produces behavior-specific effects in SHR independently of OT increases.