Date of Award

12-17-2021

Degree Type

Thesis

Degree Name

MPhil in Biological and Biomedical Sciences

First Advisor

Dr. Saara (Ahmad) Muddasir Khan

Second Advisor

Dr. Fazal Manzoor Arain

Third Advisor

Dr. Hasan Salman Siddiqi

Department

Biological and Biomedical Sciences

Abstract

Background: Depression is one of the commonest psychiatric disorders globally with significant mental disability. Diabetes has been associated with depression owing to different mechanisms including inflammation and oxidative stress. Selective serotonin reuptake inhibitors are the mainstay of treatment, however they have some side effects and are not useful in treatment resistant depression. Herbs seem to be a useful adjunct to standard treatment for major depressive disorder (MDD) amongst which chamomile and saffron have shown promising potential. Therefore, this study involves the individual and combined effect of these two herbs in the treatment of diabetes induced depression in rats. Additionally, the current study combined molecular docking and molecular dynamics (MD) calculations to evaluate the binding affinity of apigenin and safranal, active components of chamomile and saffron against depression, as putative 5HT1A and 5HT2A receptors (5HT1AR and 5HT2AR) stimulators and inhibitors respectively.
Methods: A rodent model of MDD secondary to streptozotocin-induced diabetes mellitus was made using six rat groups; healthy and diseased controls, fluoxetine, saffron, chamomile, and combined saffron and chamomile treated (n=6/group). Activity in the forced swim test, and correlations with biochemical markers like glucose, tryptophan and C-reactive protein were assessed at the end of three weeks of treatment. One-way ANOVA with post-hoc Tukey’s was employed in the statistical evaluation with significance set at p< 0.05. Using molecular docking and MD approaches, the potential of apigenin and safranal as antidepressants was tested in interacting with 5HT1AR and 5HT2AR, in the previously annotated binding sites for available classic and alternative antidepressants. The poses for the interactions were analyzed in Discovery Studio, while MD simulations were performed using AMBER16 software.
Results: The combination of chamomile and saffron treatment group fared significantly better (p< 0.05) than all other groups in terms of the anti-hyperglycemic effect, while all treatments were not significantly different in terms of improvement in tryptophan levels above the diseased controls. All treatments improved the CRP levels; however, the combination group was also significantly better than fluoxetine and the individual herb groups. Only the herb groups showed efficacy in the forced swim test (FST) with added benefits of the combination group over the healthy controls. Molecular mechanics[1]generalized Born surface area (MM-GBSA) calculations identified superior interacting capacity of apigenin over safranal for 5HT1AR and 5HT2AR with binding energies of −26.8 and −22.3; and −34.3 and −17.1 Kcal/mol, respectively over 200 nanoseconds MD simulations. Binding energy and structural analyses manifested the greater stability of apigenin compared to safranal towards 5HT1AR and 5HT2AR. Binding mode analyses displayed the capability of apigenin and safranal to form hydrogen bonds with the key amino acid residues inside the active site of 5HT1AR and 5HT2AR, respectively. Drug[1]likeness parameters showed that both apigenin, and safranal exhibit oral bioavailability, and absorbance.
Conclusion: This study shows that in comparison to treatment with fluoxetine, and the individual herbs, the combination of chamomile and saffron showed improved outcomes. Notably, apigenin, and safranal are prospective medications to treat depression, which warrants in vitro and in vivo evaluations and clinical investigations.

First Page

1

Last Page

105

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