Exploration of Neuroprotective Therapy

Table 4. Comparative table summarizing the mechanisms of action of the three natural compounds.

Pathway category	Molecular targets/Signaling pathways	Curcumin	Resveratrol	Luteolin
Anti-inflammatory	Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway	Inhibits upstream activation via the toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex	Deacetylation of the p65 subunit via sirtuin 1 (SIRT1) activation	Directly inhibits IKKβ kinase activity
Anti-aging	SIRT1/AMPK/peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)	Indirect modulation	Primary activator: Increases the NAD+/NADH ratio and SIRT1 activity	Indirect activation through the reduction of oxidative stress
Glial modulation	Microglia & astrocyte phenotype	Promotes M2 polarization by increasing triggering receptor expressed on myeloid cells 2 (TREM2)	Preventing the pro-inflammatory microglial phenotype via SIRT1	Inhibits astrocyte reactivity (A1) by reducing glial fibrillary acidic protein (GFAP)
Proteostasis	Autophagy & degradation	Increasing the expression of the enzyme neprilysin (NEP) for the degradation of Aβ	Inducing autophagy through AMPK activation	Enhancing the ERAD pathway through IRE1α/XBP1s activation
Organelle stress	Endoplasmic reticulum (ER) & mitochondrial stress	Maintaining intracellular calcium homeostasis	Protecting mitochondria from oxidative damage via nuclear factor erythroid 2-related factor 2 (Nrf2)	Key regulator: Inhibits the protein kinase RNA-activated-like endoplasmic reticulum kinase (PERK)/CHOP pathway (ER stress)
Tau pathology	GSK-3β/Tau phosphorylation	Inhibits the physical aggregation of Tau filaments	Reduces Tau acetylation, which facilitates its clearance	Direct inhibitor: Binds to the ATP-binding site of GSK-3β

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Declarations

Author contributions

NY: Conceptualization, Methodology, Supervision, Writing—review & editing. RR: Writing—original draft. MDL: Supervision, Writing—review & editing. AEN: Supervision. YB: Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

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Funding

This research was funded by the Research Directorate of Universitas Gadjah Mada under the 2025 Academic Excellence Improvement Program Scheme B (Contract No. 1908/UN1/DITLIT/Dit-Lit/PT.01.00/2025). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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