A study of the behavioral and neurogenic effect and mechanism of action of lavender essential oil and bis-7-cognitin : potential treatment options for depression

Abstract

Background: Depression is a mood disorder projected to be the highest cause of years of life lived with disability by 2030. Although a wide variety of antidepressants is currently available on the market, several concerns arise that affect the effectiveness of the treatment. Therefore, there is an urgent need to develop novel and more efficient treatment options for depression. The first step for the strategic drug design involves thinking outside the box to explore alternatives that may assist in the development of more efficient and novel pharmacological treatments. Therefore, the strategy should involve the most recent understanding of the pathophysiology of depression focusing on physiological processes not previously considered in the development of the currently available antidepressants. Understanding the pathophysiological elements involved in depression may provide a scenario to design target/network-based approaches towards drug development. Rationale of the present study: Neurogenesis has been highlighted as a promising target process to develop novel therapeutic interventions for depression. A set of considerations were established to discover novel potential treatment options for depression: to take neurogenesis as the target physiological mechanism for the evaluation of candidates with antidepressant effect, the selection of promising candidates to be included in the present study was based on the following criteria: (1) promising beneficial effect on depression based on the literature, (2) the neurogenic effect had not been previously evaluated, (3) no previous study on the molecular pathways involved in its beneficial effects on depressive symptoms and (4) at least one of the candidate(s) should act via the olfactory system in order to study the olfactory system-emotion-neurogenesis relationship in detail. The criteria enabled the identification of interesting candidates whose neurogenic effect was not previously evaluated, thereby adding to the novelty and originality of the present study. One of the candidates evaluated in the present study was lavender essential oil (LEO) that is frequently used in aromatherapy. Previous studies have evaluated LEO showing promising effects on mood in both animal studies and clinical trials. The nature of LEO and its action on the olfactory system is an interesting feature, making LEO relevant to the present study. Finally, the effect of LEO on neurogenesis has not been explored. The other candidate evaluated was Bis-(7) cognition (B7C), a dimer formed by two tacrine molecules linked by a spacer containing 2 methylene groups considered as a treatment option for Alzheimer's disease (AD). The literature review on B7C pointed out that (1) the physicochemical characteristics of B7C makes it a good candidate for the treatment of central nervous system (CNS) disorders, (2) the beneficial effects of B7C on AD animal models and the high comorbidity of AD and depression highlight a research gap that invites an evaluation of the effect of B7C on depression, (3) no previous studies have evaluated the potential antidepressant effect of B7C, and (4) the neurogenic effect of B7C has not been explored. Aim: To evaluate the behavioral and neurogenic effect of lavender essential oil and bis-(7)-cognitin in rats and to explore the molecular mechanism of action in vivo and in vitro. Methods: An extensive literature review was carried out on LEO and B7C to explore the effectiveness on depressive symptoms and the molecular targets relevant in neurological disorders respectively. As asecond stageof the project, both candidates were evaluated in vivo to assess their effect on behavior, and neurogenesis in a high corticosterone (CORT) animal model for depression. An in vitro evaluation was carried out to assess the effect of LEO and B7C on cell proliferation and explore the molecular pathways underlying their cell proliferation effect. Results: The analysis of RCT studies focused on the effect of aromatherapy on depressive symptoms demonstrated the promising effect of aromatherapy in alleviating depressive symptoms. The animal studies selected in the systematic review to assess the effectiveness of LEO on depressive symptoms clearly demonstrated the positive effect of LEO and linalool to decrease depression-like behavior compared with the effect of commercial antidepressants. The effect of LEO on behavior and neurogenesis was evaluated in a high corticosterone model in rats. The results demonstrated that treatment with LEO decreased the CORT-induced depression like behavior. Also, neurogenesis was found to be the physiological progress involved in the antidepressant effect of LEO, as treatment with LEO increased the number of positive BrdU cells in the hippocampus and subventricular zone (SVZ). Additionally, LEO reverted the CORT-induced dendritic branching atrophy in doublecortin (DCX) positive cells in the hippocampus. The overall results of the evaluation of LEO in a high-CORT animal model for depression demonstrated that LEO is a promising treatment option for the treatment of depression as it has positive effects on mood and neurogenesis. The results from the in vitro experiments demonstrated that 0.05 µl/ml LEO reverted the CORT-induced decreased cell proliferation. Also, it was demonstrated that the mechanism underlying the cell proliferation effects of LEO involved the regulation of the PI3K/Akt and MAPK/ERK signaling pathways. B7C was found to have a positive effect on behavior and neurogenesis. Also, the optimal concentration of B7C was 0.3mg/kg which was further evaluated in a high-CORT animal model for depression. Treatment with B7C showed improvement in the CORT-induced anxiety-like behavior and decreased neurogenesis. The evidence of the present study supports further investigation of B7C on mood and the molecular mechanism underlying its effect. The findings of the in vitro experiments clearly demonstrated the effect of B7C in increasing cell proliferation. Also, B7C showed a restorative effect on cell proliferation in a CORT-induced decreased cell proliferation in vitro experiment. Finally, the findings of the present study indicate that the mechanism underlying the cell proliferation effects of B7C involves the regulation of the PI3K/Akt and MAPK/ERK signaling pathways. Conclusions: LEO and B7C demonstrated to have a positive effect on mood and to increase neurogenesis. The present study is the first to address the effect of both candidates on behavior, neurogenesis and to examine the underlying mechanism of action in vitro.