This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms and critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations.
Parkinson's disease (PD) remains a neurodegenerative disorder without effective disease-modifying therapies, largely due to its multifactorial pathogenesis. We report that the natural flavonoid Astragalin (AST) concurrently addresses three core pathological processes in PD, namely dopaminergic neuron degeneration, α-synucleinopathy, and neuroinflammation, through coordinated modulation of interconnected molecular pathways. In both subacute MPTP- and chronic rotenone-induced murine PD models, AST preserved 85% of nigral tyrosine hydroxylase-positive neurons, fully prevented motor deficits, and suppressed phosphorylated α-synuclein (α-Syn) accumulation and Lewy body-like inclusion formation. Mechanistically, AST activated the BDNF-TrkB/AKT pro-survival pathway, enhanced NRF2-mediated antioxidant defense, and suppressed neuroinflammatory cascades by dual inhibition of Notch1/HES-1 and COP1-C/EBPβ signaling, leading to attenuated microglial and astrocytic activation. These findings position AST as a promising multi-target therapeutic neuroprotective candidate with disease-modifying potential, providing a structural scaffold for developing combination-inspired anti-PD strategies.
Jun Wang, Jie-Yu He, Qin Huang et al.· Free Radical Biology & Medic...· 0 citations
Neurodegenerative diseases are progressive disorders characterised by the deterioration of neuronal structure and function, ultimately leading to cognitive deficits and functional impairment. Due to neuroinflammation, oxidative stress, and mitochondrial dysfunction, neurones, which cannot regenerate themselves, are highly susceptible to degeneration. There are many possible side effects associated with traditional pharmacotherapies, although they often offer symptomatic relief, highlighting the need for safer and more effective therapeutics. Natural products such as terpenoids, a structurally diverse class of isoprenoid compounds, have shown promising neuroprotective effects. Classes of terpenoids exhibit anti-inflammatory, antioxidant, anti-apoptotic, and mitochondrialprotective effects by regulating crucial signalling cascades, including Nuclear Factor kappa B (NF- κB), Mitogen-activated protein kinase (MAPK), c-Jun N-terminal Kinase (JNK), Phosphoinositide 3-kinase/Protein kinase B (PI3K/Akt), and Nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1). Across preclinical models, representative compounds like catalpol, geniposide, artesunate, ginkgolides, alisol A 24-acetate, echinocystic acid, lycopene, and astaxanthin have demonstrated efficacy against Parkinson's disease, Alzheimer's disease, stroke, ischaemia, and haemorrhage by preserving neuronal integrity and function. Despite these promising findings, challenges such as poor bioavailability, limited blood-brain barrier penetration, metabolic instability, and a lack of standardised human safety data limit translational progress. Structural optimisation and advanced delivery systems, such as nanoparticles, cyclodextrin inclusion, combined therapeutic strategies, precision-targeted interventions, and rigorous clinical trials, may be considered future directions. In short, terpenoids have the potential to be developed as novel multitarget neurotherapeutic agents with further research to bridge preclinical promise and clinical validation.
Nidhi Gairola, Sushmita Uniyal, Jaya Martolia et al.· Mini-Reviews in Medical Chem...· 0 citations
Neurodegenerative diseases are characterized by progressive protein aggregation, mitochondrial dysfunction, neuroinflammation, and cognitive decline, yet effective mechanism‐based interventions remain limited. Sirtuin 1 (SIRT1), an NAD+‐dependent deacetylase, has emerged as a multifunctional regulator linking stress adaptation, proteostasis, and metabolic homeostasis to disease progression. Increasing evidence indicates that SIRT1 supports cognitive resilience by coordinating synaptic plasticity, autophagy–lysosomal function, mitochondrial homeostasis, and inflammatory control. In Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), reduced or dysregulated SIRT1 is associated with protein aggregation, mitochondrial dysfunction, and cognitive decline, although its effects may be disease‐ and stage‐dependent, particularly in HD. This review summarizes the structural and catalytic features of SIRT1, examines the mechanisms linking SIRT1 to cognitive impairment across major neurodegenerative diseases, and evaluates the opportunities and limitations of SIRT1‐targeted therapeutic strategies.
Jia-Bin Duan, Jia-Qiang Liu, Qing-Sheng Meng et al.· The FASEB Journal· 0 citations
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral disturbance, largely associated with amyloid-β accumulation, tau protein pathology, synaptic dysfunction, oxidative stress and neuroinflammation. Previous research emphasizes the critical roles of impaired neurogenesis and neuroplasticity in cognitive dysfunction and neurodegenerative disorders, particularly AD. This review highlights the therapeutic potential of natural products in restoring these processes. It offers a comprehensive overview of the molecular mechanisms underlying neurogenesis and synaptic plasticity, with a focus on key regulatory pathways, such as BDNF/TrkB, ERK/CREB, PI3K/Akt and neurotransmitter signaling cascades. It also shows how the disruption of these regulatory pathways, caused by AD-associated pathological factors, results in reduced neuronal regeneration and synaptic connectivity. Furthermore, it summarizes preclinical data showing that various phytochemical compounds, such as ginsenosides, epigallocatechin gallate, curcumin, resveratrol, and flavonoids can improve neural stem cell proliferation, promote neuronal differentiation, and enhance synaptic function. Despite the promising pre-clinical studies results, clinical studies evaluating natural products remain limited due to poor bioavailability, inconsistent efficacy, and methodological constraints in human studies. To overcome these limitations, new strategies such as nanotechnology-based delivery systems and advanced brain targeting approaches are being developed. Overall, natural products represent promising candidates for managing neurogenesis and neuroplasticity in AD, although further clinical studies are required to validate their therapeutic efficacy.
A. Shaheen, Mou-Sa A. Mai, Merhan O. Hindam et al.· Frontiers in Pharmacology· 2 citations
NAR has demonstrated the ability to reduce amyloid-β plaque deposition, inhibit α-synuclein aggregation, preserve dopaminergic neurons, modulate immune responses in multiple sclerosis, and improve functional recovery after spinal cord injury.
Nista Gurung, Ganesh Bohara, Nikesh Rimal et al.· Molecular Nutrition & Food R...· 0 citations
Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and cerebral ischemia, represent an escalating global health crisis with limited effective therapies. The multifactorial pathogenesis of these disorders, encompassing protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction, necessitates therapeutic approaches that target multiple pathways. Plant secondary metabolites have emerged as promising neuroprotective agents, offering multi-targeted mechanisms and favorable safety profiles. This review comprehensively examines the neuropharmacology of key secondary metabolites, including huperzine A, curcumin, resveratrol, epigallocatechin gallate (EGCG), and ginsenosides, focusing on their mechanisms against neurodegeneration. We critically evaluate evidence for neuroprotection through acetylcholinesterase inhibition, antioxidant and anti-inflammatory effects, mitochondrial protection, and modulation of protein aggregation pathways. Furthermore, we assess the therapeutic potential of these compounds in Alzheimer's disease, Parkinson's disease, and cerebral ischemia, evaluating preclinical and clinical evidence. Polyphenols, including curcumin and resveratrol, exert significant inhibitory effects on the NF-κB pathway, making them promising candidates for treating neurological disorders. Despite promising findings, challenges including bioavailability, blood-brain barrier penetration, and clinical translation persist. This review identifies research gaps and discusses emerging strategies for optimizing neuroprotective natural products for clinical application.
Moses Okpata Chukwuebuka· Global Journal of Research i...· 0 citations
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