Assessment of the mechanistic role of an Indian traditionally used ayurvedic herb Bacopa monnieri (L.)Wettst. for ameliorating oxidative stress in neuronal cells.

ETHNOPHARMACOLOGICAL RELEVANCE: This study has important ethnopharmacological implications since it systematically investigated the therapeutic potential of Bacopa monnieri(L.) Wettst. (Brahmi) in treating neurological disorders characterized by oxidative stress-a growing issue in the aging population. Bacopa monnieri, which is strongly rooted in Ayurveda, has long been recognized for its neuroprotective and cognitive advantages. The study goes beyond conventional wisdom by delving into the molecular complexities of Bacopa monnieri, particularly its active ingredient, Bacoside-A, in countering oxidative stress. The study adds to the ethnopharmacological foundation for using this herbal remedy in the context of neurodegenerative disorders by unravelling the scientific underpinnings of Bacopa monnieri's effectiveness, particularly at the molecular level, against brain damage and related conditions influenced by oxidative stress. This dual approach, which bridges traditional wisdom and modern investigation, highlights Bacopa monnieri's potential as a helpful natural remedy for oxidative stress-related neurological diseases. AIM OF THE STUDY: The aim of this study is to investigate the detailed molecular mechanism of action (in vitro, in silico and in vivo) of Bacopa monnieri (L.) Wettst. methanolic extract and its active compound, Bacoside-A, against oxidative stress in neurodegenerative disorders. MATERIALS AND METHODS: ROS generation activity, mitochondrial membrane potential, calcium deposition and apoptosis were studied through DCFDA, Rhodamine-123, FURA-2 AM and AO/EtBr staining respectively. In silico study to check the effect of Bacoside-A on the Nrf-2 and Keap1 axis was performed through molecular docking study and validated experimentally through immunofluorescence co-localization study. In vivo antioxidant activity of Bacopa monnieri extract was assessed by screening the oxidative stress markers and stress-inducing hormone levels as well as through histopathological analysis of tissues. RESULTS: The key outcome of this study is that the methanolic extract of Bacopa monnieri (BME) and its active component, Bacoside-A, protect against oxidative stress in neurodegenerative diseases. At 100 and 20 µg/ml, BME and Bacoside-A respectively quenched ROS, preserved mitochondrial membrane potential, decreased calcium deposition, and inhibited HT-22 mouse hippocampus cell death. BME and Bacoside-A regulated the Keap1 and Nrf-2 axis and their downstream antioxidant enzyme-specific genes to modify cellular antioxidant machinery. In vivo experiments utilizing rats subjected to restrained stress indicated that pre-treatment with BME (50 mg/kg) downregulated oxidative stress markers and stress-inducing hormones, and histological staining demonstrated that BME protected the neuronal cells of the Cornu Ammonis (CA1) area in the hippocampus. CONCLUSIONS: Overall, the study suggests that Bacopa monnieri(L.) Wettst. has significant potential as a natural remedy for neurodegenerative disorders, and its active compounds could be developed as new drugs for the prevention and treatment of oxidative stress-related diseases.

Nutraceutical regulation of miRNAs involved in neurodegenerative diseases and brain cancers.

The human brain is a well-connected, intricate network of neurons and supporting glial cells. Neurodegenerative diseases arise as a consequence of extensive loss of neuronal cells leading to disruption of their natural structure and function. On the contrary, rapid proliferation and growth of glial as well as neuronal cells account for the occurrence of malignancy in brain. In both cases, the molecular microenvironment holds pivotal importance in the progression of the disease. MicroRNAs (miRNA) are one of the major components of the molecular microenvironment. miRNAs are small, noncoding RNAs that control gene expression post-transcriptionally. As compared to other tissues, the brain expresses a substantially high number of miRNAs. In the early stage of neurodegeneration, miRNA expression upregulates, while in oncogenesis, miRNA expression is gradually lost. Neurodegeneration and brain cancer is presumed to be under the influence of identical pathways of cell proliferation, differentiation and cell death which are tightly regulated by miRNAs. It has been confirmed experimentally that miRNA expression can be regulated by nutraceuticals - macronutrients, micronutrients or natural products derived from food; thereby making dietary supplements immensely significant for targeting miRNAs having altered expression patterns during neurodegeneration or oncogenesis. In this review, we will discuss in detail, about the common miRNAs involved in brain cancers and neurodegenerative diseases along with the comprehensive list of miRNAs involved separately in both pathological conditions. We will also discuss the role of nutraceuticals in the regulation of those miRNAs which are involved in both of these pathological conditions.