Limonene through Attenuation of Neuroinflammation and Nitrite Level Exerts Antidepressant-Like Effect on Mouse Model of Maternal Separation Stress

Background and Aim. Depression is a social problem with high economic burden in the society. Finding an effective agent with high efficacy and few side effects is therefore needed. Involvement of neuroimmune response as well as nitric oxide (NO) has been determined in the pathophysiology of depression. Limonene is a terpene with various pharmacological properties. Thus, we aimed to evaluate antidepressant-like effect of limonene on a mouse model of maternal separation (MS) focusing on neuroinflammation and NO level in the hippocampus. Methods. Mice were randomly divided into experimental groups as follows: the control group received normal saline and MS groups received normal saline, limonene (10 and 20 mg/kg), L-NAME (10 mg/kg), L-arginine (L-arg) (75 mg/kg), limonene (10 mg/kg) plus L-NAME, and limonene (20 mg/kg) plus L-arg. Behavioral tests including the forced swimming test (FST), open field test (OFT), and splash test were performed. Finally, serum and hippocampal nitrite levels as well as the expression of inflammatory genes (IL-1β and TNF-α) in the hippocampus were measured. Results. We showed that MS caused depressive-like behavior. Treatment of MS mice with limonene reduced the duration of immobility time in FST and increases the grooming activity time in the splash test. Limonene also reduces serum and brain nitrite levels and reduces the expression of IL-1β and TNF-α in the hippocampus. We found that L-NAME potentiated the effects of a subeffective dose of limonene. Conclusion. We concluded that the antidepressant-like effects of limonene are probably mediated through inhibition of neuroinflammation and attenuation of nitrite levels in the hippocampus.