Potential therapeutic effect of Rosmarinus officinalis in a mouse model of depression

Abstract

Depression is a heterogenous and a multifactorial disorder observed with complex pathophysiology. One of the prominent hypotheses regarding depression highlights the significance of endoplasmic reticulum (ER) stress and compromised neurogenesis as key pathways contributing to the development of this disorder. Persistent ER stress has been correlated with increased inflammation, increased apoptosis and cellular atrophy. The existing approach to treating depression relies on the administration of antidepressants; nonetheless, their use is frequently linked to unfavorable side effects and response rate to treatment may vary in patients so there is a need to find such novel therapeutics that produces their potential effect with minimal side effects. In the present investigation, the therapeutic potential of Rosmarinus officinalis (R. officinalis) was assessed and compared with fluoxetine within a mouse model experiencing depression prompted by chronic unpredictable mild stress (UCMS). Six study groups were employed in this research (n=6, each). Anti-depressant like activity of R. officinalis was screened through behavioural analysis which include splash test, Y-maze test, novelty suppressed feeding test, tail suspension test (TST) and forced swim test (FST). The findings suggest that administering R. officinalis extract resulted in a significant amelioration of anhedonia, as evidenced by a significant reduction in grooming latency (p<0.01; 2.333±0.4944) and a substantial increase in grooming duration (p<0.0001; 219 ± 10.44) in the UCMS + R. officinalis-treated group during the splash test. Additionally, there was a notable improvement in behaviours associated with despair, as indicated by both the TST (immobility time: p<0.0001; 56.50 ± 10.34) and the FST (latency to immobility: p<0.0001; 64.17±6.058, immobility time: p<0.0001; 16.67 ± 6.227, and immobile episodes: p<0.0001; 6.333±1.542). However, non-significant impact of R. officinalis on anxiety and spatial memory was observed. Histopathological assessment performed through haematoxylin and eosin staining reveal the significant restoration of neuronal density in the UCMS + R. officinalis group. Moreover, the xiii levels of ATF6, an ER stress marker and NeuN, a neurogenic marker have been analysed through real-time PCR in the respective study groups. The result indicates the altered expression of these genes in the disease group. UCMS + R. officinalis-treated group significantly increased the expression of NeuN (p<0.0001; 4.8±0.09) and decrease the expression of ATF6 (p<0.0001; 2.7±0.06) as compared to UCMS-induced diseased group. The main goal of this research was also to delve into the antidepressant action of R. officinalis by utilizing network pharmacology and conducting molecular docking analyses. By interrogating network databases, potential targets linked to R. officinalis major phytochemicals and depression were identified. Sixty-four common core targets were identified between the R. officinalis compounds and depression. The result of protein-protein interaction illustrates the presence of top ten highly interacting genes in the network i.e. IL-6, MAPK1, MAPK3, ESR1, ESR2, TNF, PTGS2, EGFR, ERBB2 and BCL-2. These genes are also found to be most common in many of the depression related pathways recognized by KEGG pathway enrichment profiling. In order to assess the binding interactions of IL-6, MAPK1, MAPK3, ESR1, ESR2, TNF, PTGS2, EGFR, ERBB2, BCL-2, ATF6 and NeuN with fluoxetine and R. officinalis major bioactive compounds, an in-silico docking simulations was also performed. The result illustrates that the phytochemicals of R. officinalis showed greater binding potential than the fluoxetine with most of the target proteins. The present findings indicate the strong anti-depressant potential of R. officinalis indicating its promise as a prospective candidate for depression therapy, however further investigation on its active compounds is warranted.