Sapere

By Iqra Sharjeel

based on article: Molecular Mechanisms Underlying Neuroinflammation Intervention with Medicinal Plants: A Critical and Narrative Review of the Current Literature 

Neurodegenerative diseases (NDs) like Alzheimer’s, Parkinson’s, and multiple sclerosis are rising alongside increased life expectancy. The brain’s high metabolic demand—consuming ~3.5 mL O₂ per 100 g per minute—makes it especially vulnerable to reactive oxygen species (ROS) and inflammation. Neuroinflammation, driven by microglia and astrocyte activation, cytokine release, ROS production, and immune-cell infiltration, is implicated in neurological and psychiatric disorders, stroke, and trauma. Central to this are dysregulated signaling pathways—NF‑κB, Nrf2, NLRP3 inflammasome, and JAK/STAT—where NF‑κB, NLRP3, and JAK/STAT typically propagate inflammation, while Nrf2 counteracts it.

Given the limitations and costs of synthetic drugs, interest is growing in medicinal plants, which offer antioxidant, anti-inflammatory, and neuroprotective benefits and have been used safely for millennia. Dietary phytochemicals may delay ND onset, yet translating preclinical findings to the clinic requires focused study. Past reviews lacked systematic depth on neuroinflammation mechanisms. Building on this, the present study systematically examines recent literature to identify molecular targets, dosages, and therapeutic implications of plant-based neuroinflammation modulators.

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Key Signaling Pathways in Neuroinflammation

NF‑κB

NF‑κB is a transcription factor regulating genes tied to inflammation. In its canonical pathway, inhibitory IκB proteins are phosphorylated via kinases (IKKα/β/NEMO), releasing NF‑κB (p65/p50) to translocate into the nucleus under the influence of MyD88 and TLR signaling. A non‑canonical pathway involves NIK-mediated p100 processing to p52, forming RelB/p52 dimers. In glial cells, chronic NF‑κB activation contributes to neurodegeneration in several NDs.

Nrf2

Nrf2 controls antioxidant response-element (ARE) gene expression under oxidative stress. Normally sequestered by Keap1 and degraded, stress releases Nrf2 to enter the nucleus (activated via PI3K, PKC, MAPK, etc.), boosting antioxidant defenses (e.g., glutathione synthesis). Nrf2 also suppresses NF‑κB indirectly. In microglia, Nrf2 activation fosters anti-inflammatory (M2) phenotypes, countering ROS and inflammatory cytokines.

NLRP3 inflammasome

In response to danger signals (PAMPs/DAMPs), NF‑κB first primes NLRP3 expression. A second signal (e.g., ATP influx) triggers assembly of the NLRP3–ASC–pro‑caspase‑1 complex, leading to cleaved caspase‑1 that activates IL‑1β/IL‑18 and induces pyroptosis via Gasdermin-D. NLRP3 hyperactivation is linked to Alzheimer’s β‑amyloid pathology and Parkinson’s α‑synuclein deposits.

JAK/STAT

JAK/STAT signaling is vital for neuronal and astrocytic functions, via cytokines such as IL‑15 affecting neural stem cells. In NDs, overactive JAK2/STAT3 signaling exacerbates microglial activation and cytokine release, while inhibitors like AZD1480 reduce inflammation and neurodegeneration in animal models.

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Microglial Activation and Its Role in Neurodegeneration

Microglia (5–10% of CNS cells) adopt multiple morphologies reflecting functional states. In response to injury, they transition from surveillance (ramified) to M1 (pro-inflammatory) or M2 (anti-inflammatory) states. M1 releases NO, TNF‑α, IL‑6/1β, ROS, driving neuronal damage; M2 secretes IL‑10, TGF‑β, neurotrophic factors like BDNF, facilitating repair. Aging disrupts regulatory axes like CD200–CD200R and CX3CL1–CX3CR1, maintaining microglia in a pro-inflammatory state. Single-cell transcriptomics in Alzheimer’s highlights shifts in microglial subtypes, while α‑synuclein and NLRP3 activation underlie Parkinson’s pathology. In multiple sclerosis, microglial activation disrupts the blood–brain barrier, fueling demyelination.

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Medicinal Plants Impacting Neuroinflammation

Cleistocalyx nervosum var. paniala

In BV‑2 microglial cells, extracts (5–100 µg/mL) reduced COX‑2, iNOS, and NF‑κB activation. Preclinical studies are needed.

Curcuma longa (Turmeric)

Curcumin (12.5–200 µg/mL in vitro; 50–200 mg/kg in vivo) decreased pro-inflammatory cytokines and inhibited NF‑κB. Dose variability calls for more consistent protocols.

Cannabis sativa

Cannabinoid-rich extracts reduced inflammatory cytokines, boosted endocannabinoids, and modulated NF‑κB and NLRP3 in BV‑2 cells. In animal models, cannabis compounds demonstrated potential to reduce α‑synuclein accumulation, improve cognitive outcomes, and attenuate spinal cord inflammation. Lack of strain consistency demands standardized profiles and safety trials.

Dioscorea nipponica

Extracts (10–100 µg/mL and 60 mg/kg in vivo) reduced iNOS and COX‑2, while increasing BDNF and pCREB—suggesting cognitive benefits and mood stabilization potential.

Centipeda minima & Atractylodis rhizoma Alba

Both inhibited NF‑κB and iNOS expression in vitro/in vivo; further studies needed to dissect active phytochemicals.

Vaccinium bracteatum & Lonicera japonica

In vitro assays (2.5–20 µg/mL) showed decreased pro-inflammatory and oxidative markers. Identification of key bioactives is needed.

Bambusae caulis

Shown to upregulate HO‑1 and Nrf2 in vitro, indicating engagement of the antioxidant response; requires component analysis and dosing optimization.

Zingiberis rhizome (Ginger)

At 1–10 µg/mL, ginger extract significantly reduced NO, PGE2, COX‑2, pro-inflammatory cytokines, and suppressed NF‑κB/MAPK signaling.

Resveratrol‑enriched rice

Genetically-modified rice reduced pro-inflammatory markers in vitro; carries large-scale potential pending clinical validation.

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Challenges & Research Directions

• Preclinical & Clinical gaps: Many studies lack in vivo validation, safety data, BBB permeability studies, and standardized dosing.
• Extract variability: Environmental, genetic, and extraction differences alter phytochemical content; standardized methods are essential.
• Mechanistic understanding: Detailed molecular pathways—BBB crossing, bioavailability—remain incompletely mapped.
• Advanced methodologies:
  • Genetic tools (RNA‑seq, gene editing) to pinpoint molecular targets.
  • Immunoassays (ELISA, flow cytometry) to profile inflammatory responses.
  • Molecular docking to predict phytochemical–target interactions.
  • Comparative studies of extraction techniques to optimize yield and stability.
  • Nanomedicine: Nanocarriers (curcumin, cannabinoids) enhance delivery across the BBB, reduce dosage, and enable synergistic multi-target therapies.
  • AI-powered phytochemical screening to accelerate lead compound discovery.
  • Personalized medicine and green healthcare: Explore adaptogens and gut–brain axis modulation.
• Safety and comparative analysis: Long-term toxicity, drug interactions, and cost-benefit comparisons versus synthetic drugs require thorough study.

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Conclusions

Medicinal plants offer rich therapeutic potential against neuroinflammation, acting on multiple targets—NF‑κB inhibition, Nrf2 activation, inflammasome suppression, JAK/STAT modulation. Examples include turmeric, cannabis, ginger, and resveratrol-enhanced rice, which show promising preclinical results. However, to move toward clinical use, comprehensive preclinical validation, safety assessment, standardized protocols, and innovative delivery methods are vital. A multidisciplinary approach bridging molecular biology, pharmacology, nanotechnology, AI, and personalized medicine will be key to unlocking the green healthcare promise of medicinal plants in ND management.