Exploration of Neuroprotective Therapy

Table 2. Studies that prove that resveratrol has the potential to overcome neuroinflammation.

Researcher and year	Model	Resveratrol dosage and duration	Parameter	Key results	Conclusion
Moussa et al. 2017 [68]	Mild-moderate Alzheimer’s subjects (human, N = 119; subset analysis N = 19 vs. 19)	Up to 2 g per day (1 g twice daily), 52 weeks duration	1. CSF markers MMP-9, MDC, IL-4, FGF-2 2. Plasma MMP-10, IL-12P40, IL-12P70, RANTES 3. Mini-Mental Status Examination (MMSE) & AD Cooperative Study-Activity of Daily Living (ADCS-ADL) scores 4. CSF Aβ-42, Aβ-40, Tau	1. Significant decrease in CSF MMP-9 2. Increase in MDC, IL-4, FGF-2 in CSF 3. Increased plasma MMP-10; decreased IL-12P40, IL-12P70, RANTES 4. Slow decline in MMSE, ADCS-ADL, CSF Aβ-42; did not affect Tau	Resveratrol decreases neuro-inflammation, enhances adaptive immune responses, and stabilizes cognitive decline and AD biomarkers; sirtuin 1 (SIRT1) activation has potential as a therapeutic target
Abozaid et al. 2022 [23]	Wistar rats, AD model induced by AlCl₃ (100 mg/kg/day for 60 days)	Oral RSV-SeNPs, 200 mg/kg/day via gavage for 8 weeks (after AD formation)	1. Oxidative stress: MDA, GSH, catalase 2. AD biomarkers: Aβ-42, p-Tau 3. Neuroinflammation: IL-1β, p-STAT3 4. Cholinergic: ACh 5. Cell signaling: p-PI3K, p-GSK-3β 6. Gene expression: SIRT1, miR-134 (RT-qPCR) 7. Histopathology: hippocampus (Aβ plaques, neuronal hypoplasia vs. protection)	1. RSV-SeNPs reduce MDA, increase GSH & catalase 2. Lower Aβ-42 & p-Tau levels 3. Reduced IL-1β and p-STAT3 (decreased neuroinflammation) 4. Increased brain ACh 5. Restoring p-PI3K and p-GSK-3β to normal direction 6. Increases SIRT1 expression, suppresses miR-134 7. Histopathology: reduced Aβ plaques and neuronal degeneration in the hippocampus, as well as increased healthy neurons	RSV nano-formulation with selenium effectively ameliorated oxidative stress, neuroinflammation, cholinergic effects and AD biomarkers in Alzheimer’s mouse models. Mediated through activation of the PI3K pathway/suppressing GSK-3β, modulation of SIRT1/miR-134, and decreased
Chen et al. 2023 [25]	In vivo: 6-week-old female ICR mice (Institute of Cancer Research mice); azq: primary microglia (neonatal ICR), primary neurons; PRV (pseudorabies virus)	In vivo: Res were given oral gavage pre-treatment 7 days before PRV intranasal infection, then continued 1×/day for 3 days after infection; In vitro: Res 3.75, 7.5, 15 µg/mL [incubation 24–48 h; CCK-8 (Cell Counting Kit-8): 0–60 µg/mL]	1. Blood-brain barrier (BBB)/edema: brain water content, Evans blue extravasation; IHC MMP-2, MMP-9, ZO-1, Iba1 2. Histologi: H&E, Nissl, TUNEL (neuronal apoptosis) 3. Inflamasi/sitokin: mRNA (RT-PCR) & protein (ELISA) untuk IL-6, tumor necrosis factor-alpha (TNF-α), CCL3, CXCL10, MCP-1, IL-4, IL-10, TGF-β, NGF, GDNF 4. M1/M2 microglia: immunofluorescence & flow cytometry (CD11b, CD86 as M1; CD206 as M2); mRNA M1 markers (CD86, TNF-α, iNOS) & M2 markers (CD206, Arg-1, Ym1) 5. Co-culture: inflamasi neuron (ELISA) & apoptosis neuron (AnnexinV/PI)	1. BBB & brain edema: medium- and high-dose Res decreased brain water content; high-dose Res decreased BBB leakage; Res decreased MMP-2, MMP-9, and increased ZO-1 2. Histology & apoptosis: medium- and high-dose Res reduced neuronal damage and apoptosis 3. Cytokines & inflammation: Res decreases proinflammatory cytokines and increases anti-inflammatory and neurotrophic factors 4. Microglia polarization: Res decreases M1 and increases M2 5. Neuronal co-culture: Res decreases proinflammatory cytokines in neurons; Res increases anti-inflammatory cytokines in neurons; Res reduces neuronal apoptosis	Resveratrol protects against PRV-induced encephalitis in mouse models by repairing BBB integrity, suppressing pro-inflammatory responses, increasing anti-inflammatory cytokines & neurotrophic factors, and shifting microglia polarization from M1 phenotype to M2 phenotype, thereby reducing neuronal apoptosis. These results support the potential of Res as an adjuvant therapeutic agent in viral encephalitis

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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

Not applicable.

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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