Rena Yamauchi

β-Lactotensin and neurotensin rapidly reduce serum cholesterol via NT2 receptor

Beta-lactotensin, a neurotensin NT2 agonist derived from beta-lactoglobulin, has hypocholesterolemic activity after administration for 2 days at a dose of 30 mg/kg (i.p.) or 100 mg/kg (p.o.) for 2 days in mice fed a high-cholesterol/cholic acid diet. The onset of hypocholesterolemic activity of beta-lactotensin was observed 90 min after a single i.p. or p.o. administration at the same dose as described above. Neurotensin also induced hypocholesterolemic activity 90 min after single i.p. administration at a dose of 2 microg per mouse but was ineffective after oral administration. The rapid onset of hypocholesterolemic activities of beta-lactotensin and neurotensin was blocked by levocabastine (50 microg/kg), an NT2 antagonist, and raclopride (0.5 mg/kg), a dopamine D2 antagonist.

Characterization of β-Lactotensin, a Bioactive Peptide Derived from Bovine β-Lactoglobulin, as a Neurotensin Agonist

β-Lactotensin (β-LT: His-Ile-Arg-Leu) is an ileum-contracting peptide derived from residues No. 146-149 of bovine β-lactoglobulin. The ileum-contracting activity of β-LT was blocked by the NT1 antagonist SR48692. β-LT was selective for the neurotensin NT2 receptor while neurotensin was selective for the NT1 receptor. β-LT is the first natural ligand showing selectivity for the NT2 receptor. β-LT showed hypertensive activity after intravenous administration at a dose of 30 mg/kg in conscious rats, while neurotensin showed hypotensive activity. The hypertensive activity of β-LT was blocked by levocabastine (1 mg/kg, i.v.), an NT2 antagonist. SR48692, which blocked the hypotensive activity of neurotensin, had no effect on the hypertensive activity of β-LT. These results suggest that the hypertensive activity of β-LT is mediated by the NT2 receptor. It was concluded that the NT1 and NT2 receptors mediate the opposite effect on blood pressure.

Effect of β-lactotensin on acute stress and fear memory

Abstract β-Lactotensin (β-LT) is a bioactive peptide derived from bovine milk β-lactoglobulin and is a natural ligand for neurotensin receptors. We examined the effect of β-LT on restraint stress and fear memory in mice. Mice subjected to acute restraint stress exhibited a decreased number of head-dips and increased head-dip latency compared to non-stressed controls in the hole-board test, reflecting increased stress-induced behaviors. However, prior administration of β-LT improved the behaviors caused by stress. The anti-stress effect of β-LT was blocked by levocabastine, a neurotensin receptor subtype 2 (NTR2) antagonist. In the fear-conditioning test, the duration of freezing responses by cued fear conditioning was significantly reduced in mice administered β-LT compared with control mice. These results suggest that β-LT has an anti-stress effect and promotes the extinction of fear memory, which may be mediated by NTR2.

Antinociception induced by β-lactotensin, a neurotensin agonist peptide derived from β-lactoglobulin, is mediated by NT2 and D1 receptors

Abstract In this study, we examined the antinociceptive effect of β-lactotensin, a neurotensin agonist that has been isolated from the chymotrypsin digest of β-lactoglobulin as an ileum-contracting peptide. β-Lactotensin showed naloxone-insensitive antinociceptive activity by the tail-pinch test after i.c.v. (200 nmol/mouse) or s.c. (300 mg/kg) administration in ddY mice. Tolerance was not developed to antinociception induced by β-lactotensin after repeated s.c. administration for 5 days. The antinociceptive activity of β-lactotensin was blocked by treatment with the neurotensin NT2 receptor antisense ODN, while treatment with the NT1 receptor antisense ODN had no effect. The antinociceptive activity was also blocked by a dopamine D1 receptor antagonist, SCH23390 (1 μg/mouse, i.c.v.), while a D2 receptor antagonist, raclopride (0.5 μg/mouse, i.c.v.), did not block the activity. These results indicate that the antinociceptive activity of β-lactotensin is mediated by NT2 and D1 receptors.

Maternal enrichment affects prenatal hippocampal proliferation and open-field behaviors in female offspring mice.

The maternal environment is thought to be important for fetal brain development. However, the effects of maternal environment are not fully understood. Here, we investigated whether enrichment of the maternal environment can influence prenatal brain development and postnatal behaviors in mice. An enriched environment is a housing condition with several objects such as a running wheel, tube and ladder, which are thought to increase sensory, cognitive and motor stimulation in rodents compared with standard housing conditions. First, we measured the number of BrdU-positive cells in the hippocampal dentate gyrus of fetuses from pregnant dams housed in an enriched environment. Our results revealed that maternal enrichment influences cell proliferation in the hippocampus of female, but not male, fetuses. Second, we used the open-field test to investigate postnatal behaviors in the offspring of dams housed in the enriched environment during pregnancy. We found that maternal enrichment significantly affects the locomotor activity and time spent in the center of the open-field in female, but not male, offspring. These results indicate that maternal enrichment influences prenatal brain development and postnatal behaviors in female offspring.

The anorectic effect of neurotensin is mediated via a histamine H1 receptor in mice

Neurotensin (NT), a tridecapeptide found in the mammalian brain and peripheral tissues, induces a decrease in food intake after central administration. In this investigation, we examine whether the histaminergic system is involved in NT-induced suppression of feeding. Intracerebroventricular injection of NT (0.1-1 nmol/mouse) led to dose-dependent inhibition of food intake in fasted ddY mice. The anorectic effect induced by NT (0.1 nmol/mouse) was ameliorated upon co-administration of pyrilamine (3 nmol/mouse), an antagonist for histomine H1 receptor. The NT-induced anorectic effect was partially ameliorated in H1 knockout mice. The findings suggest that the H1 receptor in part mediates the NT-induced suppression of food intake.

Ghrelin alters postnatal endocrine secretion and behavior in mouse offspring.

Maternal bioactive substances, such as hormones and neuropeptides, are thought to be essential for fetal development. Recently, ghrelin, a gastrointestinal peptide, has been shown to pass through the rat placenta. The ghrelin receptor, growth hormone secretagogue receptor (GHS-R), has been shown to be expressed in the rat fetal central nervous system, and plasma ghrelin levels are related to birth weight in the rodent and human. In the present study, we report a role of maternal ghrelin in mouse fetal brain development. When ghrelin was administrated to pregnant mice, pups exhibited suppression of exploratory behavior in an open-field (OF) test. Control pups, however, remained for longer periods of time in the center area, correlating with exploratory behavior. Basal corticotropin-releasing hormone (CRH) plasma levels were greater in pups from ghrelin-treated dams, and did not change in response to acute restraint stress. Moreover, reduced growth hormone secretagogue receptor and neuropeptide Y mRNA expression was observed in the hypothalamus at postnatal day 3 and remained until 16 weeks of age. In addition, under physiological condition, increased maternal ghrelin plasma levels following repeated restraint stress to the dam had effect on the increase in fetal plasma acyl ghrelin levels. These results suggest that maternal ghrelin affect fetal plasma ghrelin levels and alters endocrine systems and behaviors of offspring.