Neuroprotective Properties of Plant-Based Secondary Metabolites: Molecular Insights into Therapeutics

Objectives: To explore the neuroprotective potential of secondary metabolites in mitigating neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, that focuses on their interaction with molecular targets and mechanisms involved in neuroprotection. Methods: This review synthesizes the current research literature on the pathophysiology of neurodegenerative diseases, emphasizing key mechanisms such as oxidative stress, neuroinflammation, mitochondrial dysfunction, excitotoxicity, and protein aggregation. It further examines how naturally occurring secondary metabolites from plants, fungi, and microorganisms influence these pathological pathways to exert neuroprotective effects. Data were systematically searched in PubMed, Google Scholar, and Embase for articles published in English between 2019 and 2025. Keywords included “neuroinflammation”, “secondary metabolites”, “oxidative stress”, “amyloid aggregation”, and “neuroprotection”. Screening was performed according to PRISMA guidelines. Out of 150 peer reviewed studies, 35 qualitative articles were examined in which plant flavonoids and polyphenols in models of neurodegenerative (in vitro) diseases were included. Non-English or irrelevant articles, articles about other topics, in vivo studies without in vitro data, and studies that were not making full publications available were excluded. Molecular targets of metabolites or secondary metabolites, mechanistic pathways (i.e., antioxidant, anti-inflammatory, anti-apoptotic), organelle-specific effects, bioavailability, and blood-brain barrier permeability parameters were evaluated. Findings: Some secondary metabolites (naringenin, hesperidin, quercetin, anthocyanins) have strong neuroprotective ability and one study cited improved neuronal survival rates of 40-60% and decreased inflammatory markers. The key outcome of this review is identifying these compounds as the most promising ones based on the best potency and diverse mechanism of actions, specifically because they regulate oxidative stress, neuroinflammation and protein aggregation. Major bottlenecks are low bioavailability, low blood-brain penetration, and no long-term safety data. Future area of focus should include in vivo validation studies, pharmacokinetics, target identification, in vitro and in vivo assessment, and combinational or nanotechnology-based approaches; with a long-term goal of conducting well-designed clinical trials for neurodegenerative diseases. Novelty: In contrast to prior reviews that generally consider antioxidants and anti-inflammatory actions, this review identifies naringenin, hesperidin, baicalein, and ferulic acid as the most promising neuroprotective compounds overall. By comparing the effects of these compounds in in vitro neurodegenerative models, this review highlights their relative potency, efficacy and their underlying molecular mechanisms of action. Such an approach also closes a literature gap and provides a framework for transitioning these neuroprotective candidates to clinical utility through in vivo testing, pharmacokinetics, and clinical translational studies that may lead to novel therapeutic strategies. Keywords: Neuroinflammation, Secondary metabolites, Oxidative stress, Amyloid aggregation, Polyphenols, Flavonoids