Multi-modal neuroprotection of Argemone mexicana L. against Alzheimer's disease: In vitro and in silico study.

Argemone mexicana L. is a medicinal plant, but its impact on Alzheimer's disease (AD) is right now undetermined. We intended to investigate the in-vitro anti-AD potential of leaves and flowers of A. mexicana methanol, ethanol, and ethyl extracts and to identify multi-modal anti-AD phytochemicals by computational approaches. Molecular docking of 196 phytochemicals identified three hit phytochemicals (protoberberine, protopine, and codeine) with higher binding affinity and multi-targeting ability toward AChE, BChE, BACE-1, and GSK-3ß. Further MM-GBSA assays confirmed the integrity of these phytochemicals as the hit phytochemicals. However, these phytochemicals demonstrated favorable pharmacokinetics (PK) and drugable properties having no toxicity. Molecular dynamics simulations confirmed the binding strength of the hit phytoconstituents in the active pockets of AChE, BChE, BACE-1, and GSK-3ß with multi-targeting inhibitory activities. All the extracts exhibited dose-dependent antioxidant and anti-cholinesterase activities supporting the in silico results in the context of oxidative stress and cholinergic pathways. Our results offer scientific validation of the anti-AD properties of Argemone mexicana L. and identified protoberberine, protopine, and codeine that could be used for the development of multi-modal inhibitors of AChE, BChE, BACE-1, and GSK-3ß to combat AD. Additional in vivo validation is recommended to ensure a thorough assessment in the present research.

Mitochondrial dysfunction: A notable contributor to the progression of Alzheimer's and Parkinson's disease.

Mitochondrial dysfunction remains a pivotal mechanism in manifold neurodegenerative diseases. Mitochondrial homeostasis within the cell is an essential aspect of cell biology. Mitochondria, the power-generating organelle of the cell, have a dominant role in several processes associated with genomic integrity and cellular equilibrium. They are involved in maintaining optimal cell functioning and ensuring guidance against possible DNA damage, which could lead to mutations and the onset of diseases. Conversely, system perturbations, which could be due to environmental factors or senescence, induce changes in the physiological balance and result in mitochondrial function impairment. As a result, we present a general overview of the pathological pathways involved in Alzheimer's and Parkinson's diseases caused by changes in mitochondrial homeostasis. The focal point of this review is on mitochondrial dysfunction being a significant condition in the onset of neuronal disintegration. We explain the pathways associated with the dysfunction of the mitochondria, which are common among the most recurring neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Are mitochondrial dysfunctions an early event in the progression of neuropathological processes? We discovered that mtDNA mutation is a major contributor to the metabolic pathology of most neurological disorders, causing changes in genes important for physiological homeostasis. As a result, genetic changes in presenilin, Amyloid-, ABAD, DJ-1, PINK-1, PARKIN, alpha-synuclein, and other important controlling genes occur. Therefore, we suggest possible therapeutic solutions.