Effects of 4-hydroxyisoleucine from Fenugreek Seeds on Depression-like Behavior in Socially Isolated Olfactory Bulbectomized Rats

CONTEXT: Antidepressant-like effects of (2S, 3R, 4S)-4-hydroxyisoleucine (4-HI), a major amino acid from fenugreek seeds, has been reported in the animal model of acute depression. AIMS: To evaluate effects of subacute administration of 4-HI in animal model of stress-induced depression namely socially isolated olfactory bulbectomized rats. MATERIALS AND METHODS: Bilateral olfactory bulbectomy (OBX) were induced in 30 Sprague-Dawley rats. After recovery period of 14 days, rats were randomized into five groups of 6 rats each and stressed with social isolation (individual housing). The rats were orally treated with either vehicle (OBX-Iso), positive control, fluoxetine (30 mg/kg) or 4-HI (10, 30, 100 mg/kg) once a day from day 14 onward. Separate group of rats with social isolation but without OBX (Sham-Iso) was also maintained. The behavioral depression and anxiety related parameters using open field test (OFT), sucrose intake test, novelty suppressed feeding (NSF) and forced swim test (FST), and neurochemical estimation (brain monoamines viz., serotonin and nor-adrenaline, serotonin turnover, and serum cortisol) were performed. STATISTICAL ANALYSIS USED: Data was analyzed by either two-way ANOVA (OFT and FST) or one-way ANOVA (sucrose intake test, NSF, and neurochemical estimation) followed by Dunnett's multiple comparisons test. Differences were considered significant at P < 0.05. RESULTS: The significant and dose-dependent protection from behavioral and neurochemical changes were observed in 4-HI co-administrated OBX-Iso rats. CONCLUSION: 4-HI demonstrated the antidepressant and antianxiety effects in socially isolated stress-induced OBX rats with possible involvement of multiple stress relieving mechanisms. HIGHLIGHTS OF PAPER: In this study, the subacute pretreatment of 4-HI showed strong and dose-dependent prevention of isolation stress related behavioral and neurochemical responses in olfactory bulbectomized rats. The prevention of hyperactive HPA axis in OBX-Iso stress-induced rats can be envisaged as probable mechanism of antidepressant and antianxiety effects of 4-HI. SUMMARY: Effect of 4-hydroxyisoleucine (4-HI) in olfactory bulbectomized and socially isolated (Iso) rats was evaluated; 4-HI showed significant and dose-dependent antidepressant effects during novelty suppressed feeding (NSF) and forced swim test (FST); 4-HI showed significant and dose-dependent antianxiety effects during OFT (open field test) and sucrose intake test; 4-HI showed protection from OBX-Iso stress-induced brain monoamines, serotonin turnover, and serum cortisol level elevation. Abbreviations used: SSRI: Selective Serotonin Reuptake Inhibitor; 4-HI: (2S, 3R, 4S)-4-hydroxyisoleucine; OBX: Olfactory bulbectomy; CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; OFT: Open Field Test; NSF: Novelty Suppressed Feeding; FST: Forced Swimming Test; 5HT: 5-Hydroxytryptamine; 5-HIAA: 5-Hydroxyindoleacetic Acid; NA: Nor-adrenaline; and HPA: Hypothalamic-Pituitary Adrenal.