Intra-Nasally Administered Oligopeptide Lunasin Acts as a Possible Anti-Psychotic Agent in Mice Models

Abstract

Background and Objectives: Previously we have shown that synthetic lunasin, a 43 amino acid residue-containing peptide, after its central (intracisternal) administration in mice demonstrated antagonism against dopaminergic drug behavioural effects, indicating a putative antipsychotic/anti-schizophrenic profile of lunasin. The aims of the present studies were: to test whether lunasin would show an influence on the dopaminergic system after intranasal administration, and to examine the effect(s) of lunasin on serotonin and glutamatergic systems, which could play an essential role in antipsychotic action. Materials and Methods: Lunasin was administered intra-nasally at doses 0.1 and 1 nmol/mouse in ICR mice (n = 7-8) and tested in an open field on hyperlocomotion caused by amphetamine; serotonin 5-HT 2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)- 2-aminopropane (DOI); and glutamate NMDA receptor antagonist phencyclidine. Following behavioural testing, the contents of neurotransmitters and their metabolites in brain hemispheres (n = 6-8) were assessed by ultra-high-performance liquid chromatography-time of flight mas-spectrometry (UHPLC-TOF-MS) method. Also, lunasin binding to serotonin receptors was assessed. Results: Lunasin intra-nasally fully normalized hyper-locomotion and brain monoamine levels in amphetamine- and DOI-treated mice brains. Phencyclidine behavioural effects were not influenced. In vitro receptor binding data demonstrated a low affinity of lunasin (at µM concentrations) compared with DOI (nM concentrations) for the 5-HT_2A and 5-HT_2C receptors. Conclusions: These results demonstrated, for the first time, that the intranasal administration of oligopeptide lunasin normalized mice behaviour and brain monoamine levels in experimental psychosis mice models. Its neuro-regulatory effects indicated a usefulness of this peptide molecule for the design of novel psychotropic agents.

Keywords: brain monoamines; hyper-locomotion; intranasal administration; lunasin; receptor binding.

Figure 1

Influence of lunasin i.n. on locomotor activity in an open field test in ICR mice. Drugs that produce hyperactivity, such as amphetamine (A) 3 mg/kg (a); DOI 3 mg/kg (b); and phencyclidine (PCP) 5 mg/kg (c) were administered i.p. 15 min before lunasin (LUN) doses at 0.1 or 1 nmol/mouse/5 µL or 0.9% NaCl i.n. (Control). Locomotor activity was assessed 15 min after i.n. administration and quantified as the distance travelled in cm during the 15-min test. Data are expressed as the mean ± SD, (n = 7–8). ** p < 0.01 and *** p < 0.001 vs. Control; ^^ p < 0.01 vs. A (a); # p < 0.05 vs. DOI (b).

Figure 2

Influence of lunasin i.n. on brain monoamines and their metabolite levels altered by amphetamine (A) and DOI: DA (a), HVA (b), DOPAC (c), 5-HT (d), 5-HIAA (e), and NA (f) levels (ng/g). Data are expressed as the mean ± SD, n = 6–8. * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. Control; ^ p < 0.05, ^^ p < 0.01, p < 0.001 vs. A; ## p < 0.01, ### p < 0.001 vs. DOI.