Effect of Single Oral Coingestion of GABA and Malic Acid on Postprandial GLP-1, Glucose, and Insulin Responses in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

SCOPE: This study examines whether coingestion of γ-aminobutyric acid (GABA) and malic acid (MA) before meals enhances glucagon-like peptide-1 (GLP-1) secretion, and which affects subsequent insulin and glycemic responses in humans. METHODS AND RESULTS: Initially, a murine enteroendocrine STC-1 cell line is used to verify coadministration of GABA and MA synergistically induces GLP-1 secretion. Next, 22 healthy adults are given water (50 mL) containing 400 mg GABA and 400 mg MA (Test), or only 400 mg citric acid (CA) (Placebo) 20 min before meal tolerance test (MTT). Interval blood samples are taken postprandially over 180 min to determine GLP-1, insulin, and glucose responses. By comparison to preload of Placebo, preload of Test significantly increases plasma GLP-1 (total/active) levels (incremental area under the curve by 1.2- and 1.6-fold), respectively. However, there are no significant differences in postprandial blood glucose and insulin. CONCLUSION: Coingestion of GABA and MA before meals enhances postprandial GLP-1 secretion. Future studies should explore optimal dosage regimens to find the efficacy of the mixture on insulin and glycemic response.

Synergistic anti-depressive effect of combination treatment of Brexpiprazole and selective serotonin reuptake inhibitors on forced swimming test in mice.

AIM: Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. METHODS: Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data. RESULTS: Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). CONCLUSION: Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.

Prenatal methotrexate injection increases behaviors possibly associated with depression and/or autism in rat offspring; A new animal model for mental disorder, based on folate metabolism deficit during pregnancy.

BACKGROUND: Deficiency of folate, an essential vitamin for DNA synthesis and methylation, is reported as a risk factor for mental disorders. Considering a possibility that folate metabolism deficit during pregnancy may disturb CNS development and increase mental disorders in offspring, we treated pregnant rats with methotrexate (MTX), an inhibitor of folate metabolic enzyme, and evaluated offspring behaviors. METHODS: Saline or MTX was intraperitoneally administered to female SD rats on gestational day 17. Offspring behaviors were evaluated during approximately 6-9 weeks old; prepulse inhibition (PPI), social interaction (SI), locomotor activity (LA), and forced swimming test (FST) for evaluation of schizophrenia, depression, and autism related behaviors; the elevated plus maze (EPM) and the light-dark box (LD) test for evaluation of anxiety. RESULTS: Compared to saline-treated group, MTX-treated group showed decrease of SI and increase of immobility time in FST. In addition, increases of time spent in the light box and shuttling between the light-dark boxes were observed in LD test. On the other hand, no changes were confirmed in EPM, LA, and PPI. CONCLUSION: Decrease of SI and increase of immobility time in FST may suggest association of this animal model with depression and/or autism. Increase of time spent in the light box and shuttling between the light-dark boxes may indicate changes in anxiety or cognitive level to environment, or repetitive behaviors in autism. Although further studies are warranted to characterize this animal model, at least we can say that prenatal MTX exposure, possibly causing folate metabolism deficit, affects offspring behaviors.