Natural Bioactive Molecules as Neuromedicines for the Treatment/Prevention of Neurodegenerative Diseases

Neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis, Huntington’s disease, and motor neuron disease are major neurological disorders marked by progressive neuronal loss. Central to their pathogenesis are oxidative stress (OS), neuroinflammation, excitotoxicity, mitochondrial dysfunction, and protein misfolding/aggregation. The brain’s high oxygen consumption (~20% of total), rich content of oxidizable PUFAs, presence of redox-active metals, and reliance on mitochondrial oxidative metabolism elevate reactive oxygen/nitrogen species (ROS/RNS) burden. Oxysterols (e.g., 24-hydroxycholesterol, 7-ketocholesterol, 27-hydroxycholesterol) and lipid peroxidation products (HNE, MDA, acrolein, isoprostanes/neuroprostanes) damage macromolecules and promote amyloidogenesis and inflammation, contributing to AD and PD pathology. Lifestyle, diet, environmental factors, and stress further modulate risk. Current pharmacotherapies are largely symptomatic; thus, natural bioactives with antioxidant, anti-inflammatory, and neuromodulatory properties are being explored as preventive/therapeutic strategies to bolster the brain’s limited antioxidative/regenerative capacity.

The Review surveys major classes of bioactive compounds and their neurorelevance: - Phenolic compounds (polyphenols/flavonoids such as quercetin, catechins, resveratrol, curcumin, apigenin): exhibit strong antioxidant, metal-chelating, anti-inflammatory, and anti-amyloid activities; protect against oxysterol-induced mitochondrial dysfunction and ROS; inhibit key enzymes (AChE/BChE, tyrosinase, α-amylase/α-glucosidase) relevant to AD and metabolic comorbidities. - Carotenoids (lutein, zeaxanthin, lycopene, β-carotene, β-cryptoxanthin): antioxidant, anti-inflammatory, and autophagy-modulatory effects; some cross the blood–brain barrier (e.g., lycopene), attenuating Aβ toxicity, mitochondrial dysfunction, and inflammatory signaling (TLR4/NF-κB) and correlating inversely with disease progression markers. - Essential oils (EOs; e.g., α/β-pinene, 1,8-cineole, camphor, carvone, thymol, carvacrol): besides antimicrobial properties, show cholinesterase inhibition, metal chelation, antioxidant/anti-inflammatory activities; via olfactory pathways and direct biochemical modulation, EOs improve cognition and reduce Aβ toxicity in preclinical models. - Fatty acids: omega-3 and omega-6 PUFAs are essential for CNS development, synaptic plasticity, mitochondrial biogenesis, and gene regulation (ATP metabolism); deficiency impairs brain function; DHA and its mediators (NPD1, synaptamides) are neuroprotective; ω-3s mitigate OS, neuroinflammation, and amyloid/tau pathologies in models. - Phytosterols (β-sitosterol, campesterol, stigmasterol, brassicasterol, ergosterol, lupeol, daucosterol): structurally akin to cholesterol, cross BBB, modulate cholesterol homeostasis; reduce Aβ generation (effects on APP processing and γ-secretase), promote neural stem cell proliferation (daucosterol via IGF1-AKT), and inhibit cholinesterases/BACE1 in vitro. - Tocopherols (vitamin E isoforms; α-tocopherol prominent): lipid-soluble antioxidants with gene-regulatory and signaling roles; reduce Aβ-induced cytotoxicity and OS, modulate APP processing toward non-amyloidogenic pathways, and influence autophagy; dietary vitamin E intake associates inversely with AD incidence. Sections detail bioactives’ effects across NDDs (AD, PD, MND/ALS, HD), including enzyme inhibition, anti-aggregate mechanisms (ubiquitin–proteasome and autophagy–lysosome pathways), mitochondrial protection, anti-inflammatory signaling (TLR4, NF-κB, MAPKs), and pro-survival pathway modulation (PI3K/Akt; suppression of JNK/p53). Combination strategies (vitamins, ω-3s with polyphenols/vitamin D/B) show synergistic antioxidative and anti-inflammatory benefits.

- Alzheimer’s disease (AD): - Phenolics: Plant extracts rich in chlorogenic acid, hesperidin, kaempferol, apigenin, quercetin, rutin, gallic/caffeic acids inhibited AChE/BChE and carbohydrate-hydrolyzing enzymes (e.g., Sesamia cretica: AChE IC50 347.22 μg/mL; BChE IC50 378.79 μg/mL; α-amylase IC50 126.90 μg/mL; α-glucosidase IC50 139.66 μg/mL). Maple syrup extract reduced neuroinflammatory proteins (SOCS6, TREM2, TMEM173) in 3xTg-AD mice. Grape seed polyphenols increased brain levels of microbiota-derived phenolic acids that interfered with Aβ aggregation. - Carotenoids: Higher serum lutein+zeaxanthin and lycopene associated with lower AD mortality. RBC lutein inversely correlated with peroxidized phospholipids in AD patients. β-carotene improved cognition and reduced Aβ with AChE binding (in silico). Lycopene improved memory/learning, reduced proinflammatory cytokines (TNF-α, IL-1β, IL-6), and inhibited TLR4/NF-κB signaling at the choroid plexus; decreased Aβ secretion (C. elegans, SH-SY5Y APPsw), downregulated APP, and protected against Cu/H2O2-induced OS; mitigated mitochondrial dysfunction (mPTP opening, Cyt c release, MMP loss), reduced ROS and Nucling expression; improved antioxidant status (↑GSH-Px, ↓MDA) and reduced tau hyperphosphorylation in P301L mice. - Essential oils: Pinus halepensis EO reversed Aβ1–42-induced memory deficits and normalized hippocampal AChE/oxidant–antioxidant balance; Rosmarinus officinalis EO (1,8-cineole/1,8-pinene) improved behavior; Mentha spicata, Tetraclinis articulata, Salvia miltiorrhiza EOs showed AChE inhibition, antioxidant effects, reduced MDA, improved cognition; Lavandula luisieri EO component inhibited BACE1; rose EO reduced Aβ deposits via SKN-1 pathway (C. elegans). - Fatty acids: ω-3 FAs decreased ROS, apoptosis, and lipid peroxidation while increasing SOD, GPx, catalase in brain endothelial cells; developmental ω-3 deficiency caused long-term synaptic marker changes and altered AA degradation; endogenous ω-3s reduced Aβ plaques, protected vasculature, improved survival in tau models; deuterated PUFAs reduced brain lipid peroxidation and Aβ levels. - Phytosterols: β-sitosterol inhibited AChE/BChE (IC50 ~50–55 mg/mL) and improved cognition/motor coordination in transgenic AD models; lupeol predicted to inhibit BACE1 via H-bonding to catalytic residues. - Tocopherols: α-tocopherol decreased Aβ cytotoxicity, shifted APP toward non-amyloidogenic processing, modulated autophagy and cell-cycle genes, restored Nrf2, and reduced iNOS; α-tocopherol plus etodolac improved BBB, synaptic markers, shifted APP processing, and reduced OS/neuroinflammation in 5XFAD mice; α-tocopherol quinone improved memory and reduced Aβ oligomers and cytokines; higher dietary vitamin E associated with lower AD incidence. - Parkinson’s disease (PD): - Phenolics: Curcumin and naringenin protected TH+ neurons and striatal dopamine in 6-OHDA models; EGCG/green tea reduced nNOS and protected against MPTP toxicity; L-DOPA enriched in fava bean sprouts increased antioxidant activity. - Carotenoids: PD patients had lower serum lycopene and α/β-carotenes correlating inversely with disease stage/UPDRS. Lycopene protected against MPTP- and rotenone-induced OS, apoptosis (↓caspase-3/8/9, Bax; ↑Bcl-2), preserved dopamine, improved motor/cognition, reduced MDA (−24%) and restored GSH/SOD. - Essential oils: Eplingiella fruticosa EO, especially when complexed with β-cyclodextrin, reduced lipid peroxidation, dyskinesia, memory deficits, and dopaminergic depletion in SN/striatum. - Fatty acids: ω-3 PUFAs protected SN dopaminergic neurons, reduced NO, TNF-α, IFN-γ, microgliosis/astrogliosis, and improved behavior; fish oil reduced iNOS and glial reactivity in 6-OHDA models; hydroxylated DHA derivative (DHAH) showed strong antioxidant and anti-inflammatory effects. - Motor neuron diseases (ALS/MND): - Phenolics: Ginkgo biloba and ginseng extracts improved motor function and survival in SOD1 transgenic mice; genistein delayed disease onset and reduced mortality; EGCG delayed onset and increased motor neurons/survival (via PI3K/Akt, ↓caspase-3, ↓mitochondrial damage); resveratrol increased SIRT1, ATP, cell viability, reduced apoptosis, and upregulated Hsp70/Hsp25, improving survival in G93A-SOD1 models. - Lipid metabolism: TDP-43 Drosophila model showed altered carnitine shuttle/β-oxidation; β-hydroxybutyrate or medium-chain FAs improved locomotion, suggesting metabolic therapeutic strategies. - Huntington’s disease (HD): - Carotenoids: Lutein and lycopene ameliorated 3-NP-induced OS, mitochondrial dysfunction, and behavioral deficits; lycopene plus quercetin synergized to restore locomotion/body weight and reduce anxiety/depression. - Fatty acids: Essential FAs/PUFAs improved motor scales in patients and protected transgenic mice from motor deficits; proposed mechanisms include HDAC inhibition, reduced polyQ aggregation, and enhanced proteostasis. - Combinational bioactives: Vitamin complexes (ascorbic acid, α-tocopherol, β-carotene) reduced ROS and proinflammatory cytokines in AD patient cells; ω-3 PUFAs synergize with vitamin D3, B vitamins, curcumin, and resveratrol for multidirectional anti-inflammatory action.

This Review synthesizes evidence that natural bioactives target multiple convergent pathways implicated in NDDs: suppression of oxidative/nitrosative stress, modulation of neuroinflammation (TLR4/NF-κB/MAPK), restoration of mitochondrial function and biogenesis, regulation of calcium homeostasis and excitotoxicity, inhibition of protein aggregation with enhanced clearance (ubiquitin–proteasome and autophagy–lysosome systems), and rebalancing of pro-death/pro-survival signaling (inhibiting JNK/p53; activating PI3K/Akt; promoting Nrf2-regulated antioxidant genes). Findings across cell and animal models of AD, PD, ALS, and HD demonstrate that phenolics, carotenoids, essential oils, tocopherols, phytosterols, and ω-3 PUFAs can improve cognitive and motor outcomes, reduce pathological hallmarks (Aβ/tau/α-synuclein toxicity, lipid peroxidation, neuroinflammatory mediators), and support neurogenesis and synaptic integrity. Combinational approaches yield synergistic antioxidative and anti-inflammatory benefits, underscoring the rationale for dietary patterns or multi-nutrient interventions. While mechanistic breadth suggests high translational potential, clinical validation remains limited; optimizing bioavailability (e.g., via nanocarriers), BBB penetration, dosing, and safety profiles is crucial for neuromedicine development.

NDDs involve multifactorial dysfunctions—including oxidative stress, neuroinflammation, mitochondrial impairment, and protein aggregation—against a backdrop of limited endogenous neuroprotection. Dietary bioactive compounds offer complementary neuroprotective strategies by enhancing antioxidant defenses, modulating inflammatory and apoptotic pathways, improving mitochondrial function, and facilitating protein clearance. Preclinical evidence supports benefits of phenolics, carotenoids, essential oils, ω-3 PUFAs, phytosterols, and tocopherols in mitigating AD, PD, ALS, and HD pathologies. Early synergistic data from combined bioactive interventions further suggest additive benefits. Future work should clarify molecular mechanisms, improve delivery and bioavailability (including brain-targeted systems), and expand well-designed clinical trials to translate these bioactives into safe, effective neuromedicines.

- The article is a narrative Review; no standardized systematic search or meta-analytic synthesis is presented. - Evidence base is dominated by in vitro and animal studies; human clinical data are scarce and heterogeneous. - Dosing, formulation, and bioavailability (BBB penetration) vary widely and are not standardized; many compounds face pharmacokinetic limitations. - Potential confounders (dietary patterns, comorbidities, genetics such as APOE status) limit generalizability of observational associations. - The Review explicitly excludes chemotherapy and cancer-related effects of bioactives; it does not provide detailed risk/benefit or safety analyses for long-term use. - Publication bias toward positive findings cannot be excluded.