ABSTRACT
One of the primary therapeutic approaches for managing Alzheimer's disease (AD) involves the modulation of Acetylcholine esterase (AChE) activity to elevate acetylcholine (ACh) levels inside the brain. The current study employed computational chemistry approaches to evaluate the inhibitory effects of CTN on AChE. The docking results showed that Citronellal (CTN) and standard Donepezil (DON) have a binding affinity of -6.5 and -9.2 Kcal/mol, respectively, towards AChE. Further studies using molecular dynamics (MD) simulations were carried out on these two compounds. Binding free energy calculations and ligand-protein binding patterns suggested that CTN has a binding affinity of -12.2078. In contrast, DON has a much stronger binding relationship of -47.9969, indicating that the standard DON has a much higher binding affinity than CTN for AChE. In an in vivo study, Alzheimer-type dementia was induced in mice by scopolamine (1.5 mg/kg/day i.p) for 14 days. CTN was administered (25 and 50 mg/kg. i.p) along with scopolamine (SCO) administration. DON (0.5 mg/kg orally) was used as a reference drug. CTN administration significantly improved the mice's behavior as evaluated by the Morris water maze test, evident from decreased escape latency to 65.4%, and in the CPS test, apparent from reduced escape latency to 69.8% compared to the positive control mice. Moreover, CTN significantly increased the activities of antioxidant enzymes such as catalase and superoxide dismutase (SOD) compared to SCO. Furthermore, CTN administration significantly decreased SCO-induced elevated AChE levels in mice. These results were supported by histopathological and in silico molecular docking studies. CTN may be a potential antioxidant and neuroprotective supplement.
ABSTRACT
Most commonly inherited bleeding disorder, first described in Aland Islands by Erik von Willebrand. It occurs as a result of decrease in plasma levels or defect in von Willebrand factor which is a large multimeric glycoprotein. Monomers of this glycoprotein undergo N-glycosylation to form dimers which get arranged to give multimers. Binding with plasma proteins (especially factor VIII) is the main function of von Willebrand factor. The disease is of two forms: Inherited and acquired forms. Inherited forms are of three major types. They are type 1, type 2, and type 3; in which type 2 is sub-divided into 2A, 2B, 2M, 2N. Type 1 is more prevalent than all other types. Mucocutaneous bleeding is mild in type 1 whereas it is mild to moderate in types 2A, 2B, and 2M. Type 2N has similar symptoms of haemophilia. The pathophysiology of each type depends on the qualitative or quantitative defects in von Willebrand factor. The diagnosis is based on von Willebrand factor antigen, von Willebrand factor activity assay, FVIII coagulant activity and some other additional tests. Results should be analyzed within the context of blood group. von Willebrand factor multimer analysis is essential for typing and sub typing the disease. The management of the disease involves replacement therapy, non-replacement therapy and other therapies that include antifibrinolytics and topical agents.
