Isolation, Characterization, and In Silico Interaction Studies of Bioactive Compounds from Caesalpinia bonducella with Target Proteins Involved in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by memory loss, cognitive deterioration, and neuropsychiatric symptoms. Various drug targets implicated in AD are amyloid beta peptides, cholinesterase enzymes, and anti-amylogenic protein. Medicinal plants derived phytochemical constituents provide a vast pool of diverse compounds as a source of novel drugs. In view of this, the Caesalpinia bonducella seed extract and its active phytoconstituents were used to study the disease-modifying effects in Alzheimer's disease. The present study successfully demonstrated the therapeutic potential of various phytochemicals as it binds to multiple drug targets, resulting in inhibition of acetylcholinesterase (AChE) enzyme, butyrylcholinesterase (BuChE), BACE-1 enzyme, and anti-amylogenic protein as indicated by docking analysis. In conclusion, phytochemicals identified can be used as a suitable lead to developing a molecule that might have multi-targeted directed ligand (MTDL) potential and disease amelioration effects in Alzheimer's disease.

Chlorogenic Acid: a Polyphenol from Coffee Rendered Neuroprotection Against Rotenone-Induced Parkinson's Disease by GLP-1 Secretion.

Parkinson's disease (PD) is a chronic motor disorder, characterized by progressive loss of dopaminergic neurons. Numerous studies suggest that glucagon-like peptide-1 (GLP-1) secretagogue has a neuroprotective role in PD models. The present study evaluated potential of coffee bioactive compounds in terms of their ability to bind GPR-40/43 and tested the neuroprotective effect of best candidate on rotenone-induced PD mice acting via GLP-1 release. In silico molecular docking followed by binding free energy calculation revealed that chlorogenic acid (CGA) has a strong binding affinity for GPR-40/43 in comparison to other bioactive polyphenols. Molecular dynamics simulation studies revealed stable nature of GPR40-CGA and GPR43-CGA interaction and also provided information about the amino acid residues involved in binding. Subsequently, in vitro studies demonstrated that CGA-induced secretion of GLP-1 via enhancing cAMP levels in GLUTag cells. Furthermore, in vivo experiments utilizing rotenone-induced mouse model of PD revealed a significant rise in plasma GLP-1 after CGA administration (50 mg/kg, orally for 13 weeks) with concomitant increase in colonic GPR-40 and GPR-43 mRNA expression. CGA treatment also prevented rotenone-induced motor and cognitive impairments and significantly restored the rotenone-induced oxidative stress. Meanwhile, western blot results confirmed that CGA treatment downregulated rotenone-induced phosphorylated alpha-synuclein levels by upregulating PI3K/AKT signaling and inactivating GSK-3ß through the release of GLP-1. CGA treatment ameliorated rotenone-induced dopaminergic nerve degeneration and alpha-synuclein accumulation in substantia nigra and augmented mean density of dopaminergic nerve fibers in striatum. These findings demonstrated novel biological function of CGA as a GLP-1 secretagogue. An increase in endogenous GLP-1 may render neuroprotection against a rotenone mouse model of PD and has the potential to be used as a neuroprotective agent in management of PD.