Exploring the Antidepressant Effects of Luteolin in Mice Model of Depression

Abstract

Depression is a complex and heterogenous mental health condition which affects the overall well-being of an individual by influencing thoughts, emotions, sleep, behavior, and physical health. Reports from the world health organization (WHO) have affirmed that the global impact of depression is substantially increasing to the level that it is anticipated that by 2020, it will become the primary cause of disease worldwide. Currently, the treatment of depression involves selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic and tetracyclic antidepressants. These synthetic antidepressants, although widely prescribed, have significant limitations since they focus exclusively on one aspect of pathogenesis, resulting in the majority of them exhibiting a slow-acting nature. Moreover, they have multiple side effects that include insomnia, nausea, weight changes and sexual dysfunction. In contrast, natural plant-based flavonoid compounds having lesser side effects are known to produce anti-depressant like effects by targeting multiple pathways simultaneously. The study explored the effect of intraperitoneal administration of 10mg/kg Luteolin (LUT) on nine weeks of unpredictable chronic mild stress (UCMS) mouse model of depression in comparison with Fluoxetine (FXT). The mice were assigned randomly to six distinct study groups, with each group consisting of six mice (n=6). Coat state was examined each week as an indicator of stress. The UCMS group showed significantly altered coat state from week 4 (1.50±0.183) (p<0.001) till week 9 (1.583±0.154) (p<0.0001). The chronic LUT treatment showed significant (p<0.01) improvement in the coat state in the ninth week of UCMS (0.583±0.154). Behavioral tests were carried out to evaluate the impact of UCMS and LUT on anhedonia, anxiety, short-term spatial memory, helplessness, and behavioral 2 despair through SST, NSFT, Y-maze test, TST, and FST. The LUT treated UCMS group indicated significantly (p<0.0001) reduced anhedonia by increasing the grooming time (185±9.473 seconds) and decreasing the latency to initiate grooming behavior (p<0.001) (2±0.4472 seconds). The present study however showed no significant impairment in anxiety and short-term spatial memory in UCMS in comparison to control group. The results in TST indicated significant reduction (p<0.0001) in immobility time in UCMS+LUT treated group when compared to UCMS (98±9.2 seconds). The latency to immobility was significantly (p<0.05) increased in FST after LUT treatment (29±3.5 seconds) while the immobility time (p<0.0001) (20±5.3) and number of immobile episodes (p<0.001) (8.8±1.5) were significantly reduced when compared to UCMS group. Histopathological assessment using hematoxylin and eosin staining showed significant (p<0.0001) reduction in neuronal cells in the hippocampal dentate gyrus area in UCMS treated group (13±0.865), however the LUT treated UCMS group significantly (p<0.0001) restored this neuronal damage (25.00±1.683). For investigating the role of LUT on neurogenesis and endoplasmic reticulum (ER) stress, the expression levels of NeuN and ATF6 were examined through real time quantitative PCR. The LUT treated UCMS group (1.0±0.030) showed significant (p<0.01) improvement in NeuN expression in comparison to UCMS group (0.38±0.051). The ATF6 levels were significantly (p<0.001) decreased after LUT administration in UCMS group (3.3±0.018) indicating its potential role in neurogenesis by inhibiting the ER stress. The results of the study strongly indicated the potential antidepressant effects of LUT by reducing anhedonia and improving helplessness and behavioral despair through behavioral 3 analysis in UCMS model of depression. Meanwhile, it also exhibits neuroprotective role by significantly improving neurogenesis along with enhancing the NeuN expression in the hippocampus. The study also suggests its potential involvement in alleviating the observed ER stress in depression. Hence, LUT can serve as an effective treatment strategy for depression