Osamu Nakagawasai

Opioid receptors and their endogenous ligands are novel targets for the treatment of depression. The nociception (NOP) receptor is structurally similar to the opioid receptor, but NOP is known to have a low affinity for the opioid receptor subtypes μ, δ, and κ. In previous studies, we synthesized peptides with a high affinity for opioid receptors and investigated their antidepressant-like effects in mice. However, we have not yet examined whether NOP-related analogs have antidepressant-like effects. Herein, we synthesized NOP analogs (peptide-1–peptide-8) by solid-phase peptide synthesis using the 9-fluorenylmethyloxycarbony (Fmoc) method with Acetyl-Arg-Tyr-Tyr-Arg-Ile-Arg-NH2 (Ac-RYYRIR-NH2) as the lead compound. We examined the affinities and antagonistic activities of the analogs for the NOP receptor using receptor-binding and mouse vas deferens assays, and their effects on the duration of immobile behavior in a tail suspension test. Peptide-6 showed a high affinity and antagonistic activity for the NOP receptor. The intracerebroventricular administration of peptide-6 in mice shortened the duration of immobile behavior, whereas the co-administration of NOP inhibited this effect. Moreover, intracerebroventricular administration of the selective NOP receptor antagonist J-113397 showed antidepressant-like effects in mice. These data suggest that peptide-6 exerts an antidepressant-like effect via inactivation of the central NOP receptor in mice and may represent a lead compound for the development of antidepressant drugs in the future.

Globin digest (GD) inhibits dietary hypertriglyceridemia; however, its effects on physical fatigue remain unknown. Therefore, this study aimed to investigate the potential anti-fatigue effects of GD. Repeated administration of GD and valine (Val)-Val-tyrosine (Tyr)-proline (Pro), a component of GD, for five days prevented the forced walking-induced decrease in locomotion. Furthermore, GD treatment reversed the forced walking-induced increase in blood lactate levels in mice and increased phosphorylated AMP-activated protein kinase (p-AMPK) in the soleus muscle, suggesting that the anti-fatigue effect of GD involves AMPK activation in the soleus muscle through reduced blood lactate.

Angiotensin (Ang)-converting-enzyme (ACE) 2 converts Ang II into Ang (1–7), which in turn acts on MAS receptors (ACE2/Ang (1–7)/MAS receptors pathway). This pathway has neuroprotective properties, making it a potential therapeutic target for psychiatric disorders such as depression. Thus, we examined the effects of diminazene aceturate (DIZE), an ACE2 activator, on depressive-like behavior using behavioral, pharmacological, and biochemical assays. To determine whether DIZE or Ang (1–7) produce antidepressant-like effects, we measured the duration of immobility of mice in the tail suspension test following their intracerebroventricular administration. Next, we measured the levels of ACE2 activation in the cerebral cortex, prefrontal cortex, hippocampus, and amygdala after DIZE injection, and examined which cell types, including neurons, microglia, and astrocytes, express ACE2 in the hippocampus using immunofluorescence. Administration of DIZE or Ang (1–7) significantly shortened the duration of immobility time in the tail suspension test, while this effect was inhibited by the co-administration of the MAS receptor antagonist A779. DIZE activated ACE2 in the hippocampus. ACE2 was localized to neurons, astrocytes, and microglia in the hippocampus. In conclusion, these results suggest that DIZE may act on ACE2-positive cells in the hippocampus where it increases the activity of ACE2, thereby enhancing signaling of the ACE2/Ang (1–7)/MAS receptor pathway and resulting in antidepressant-like effects.