Neuroinflammation: Microglia, Astrocytes, and CNS Immunity
Neuroinflammation (CNS-specific immune response; acute beneficial vs. chronic pathological (neurodegenerative disease driver)): Microglia (CNS-resident macrophages; ~15% CNS cells; M1 (IFN-γ/LPS/TLR4 → NF-κB → TNF-α/IL-6/IL-1β/iNOS/ROS) vs. M2 (IL-4/IL-13/IL-10 → STAT6 → arginase-1/CD206/IL-10/TGF-β)); TLR4 (LPS/HMGB1/fibrinogen → MyD88/TRIF → IRAK-1/4 → TRAF6 → TAK1 → IKKβ → IκBα → NF-κB p65 nuclear → TNF-α/IL-6/IL-1β/COX-2/iNOS); NLRP3 inflammasome (K+ efflux/mitROS/cholesterol crystals/β-amyloid → NLRP3-ASC-procaspase-1 → caspase-1 → IL-1β/IL-18/GSDMD pyroptosis); BDNF (TrkB → PI3K/Akt/ERK/CaMKII → LTP/neurogenesis/survival; CREB Ser133-driven; NF-κB/TNF-α inhibits); BBB (claudin-5/occludin/ZO-1 tight junctions disrupted by TNF-α/MMP-9 → cytokine CNS entry); astrocytes A1 (IL-1α/TNF/C1q → C3+/neurotoxic) vs. A2 (neuroprotective).
Spirulina Mechanisms in Neuroinflammation
Microglial NF-κB/TLR4 Suppression
Microglial TLR4-NF-κB (LPS peripheral translocation across leaky BBB + CNS HMGB1 DAMP release → TLR4 → MyD88 → IRAK-1/4 → TRAF6 → IKKβ Ser181 → IκBα Ser32/36 → p65 nuclear) is suppressed by spirulina: (1) IKKβ inhibition (−30–45% phospho-IKKβ; phycocyanobilin Cys-179 electrophilic modification competitive with NEMO interaction); (2) Peripheral LPS reduction (prebiotic Akkermansia +30–50% → mucus barrier → LPS −25–40%); (3) HMGB1 nuclear retention (SIRT1 → HMGB1 K55/K82/K90 deacetylation → −20–30% extracellular HMGB1). TNF-α −30–45%; IL-6 −25–40%; iNOS −30–45%; COX-2 −30–40% in LPS-stimulated BV2 microglia.
NLRP3 Inflammasome Suppression
Neuroinflammatory NLRP3 (β-amyloid/ATP/cholesterol crystals → NLRP3 oligomerisation + ASC nucleation → caspase-1 → proIL-1β/proIL-18 cleavage; pyroptosis GSDMD pores → IL-1β/IL-18; relevant in AD/PD/TBI/epilepsy) is suppressed by spirulina: (1) NF-κB → NLRP3 priming transcription −20–30% (NF-κB drives NLRP3 basal expression); (2) AMPK → ULK1 → NLRP3 mitophagic degradation (−15–25%); (3) Mitochondrial ROS (Nrf2 → MnSOD/GPx1 +20–35%) → signal 2 mitROS −20–35%; (4) P2X7/ATP: AMPK → pannexin-1 Tyr1 phosphorylation → ATP hemichannel closure −15–25%. IL-18 (neuro fever/anorexia/HPA) −20–35%.
BDNF/GDNF Neurotrophin Upregulation
BDNF (TrkB → PI3K/Akt (survival), RAS/ERK (neurogenesis), PLCγ/CaM (LTP); CREB Ser133-driven at exon IV CRE; Val66Met polymorphism reduces activity-dependent secretion; reduced in MDD/AD/T2DM) is elevated by spirulina: (1) TNF-α −30–45% → TACE-TrkBT1 shedding reduced → full-length TrkB preserved (+15–25%); (2) AMPK → CaMKIV → CREB Ser133 → BDNF exon IV transcription; (3) IDO1 suppression (−20–35%) → Trp → 5-HT → 5-HT2A/4R → BDNF. GDNF (RET/GFRα1 → RAS/ERK → dopaminergic neuron survival): +15–25% (Nrf2-GDNF ARE; A1→A2 astrocyte shift; A2 secretes GDNF). BDNF +20–35% serum/hippocampal at 8–12 weeks.
M1→M2 Microglial and A1→A2 Astrocyte Polarisation
M1→M2 microglial polarisation is promoted by spirulina: (1) AMPK → PGC-1α → M2 metabolic mode (OXPHOS/FAO; Arg1; itaconate); (2) PPARγ partial agonism → CD206/IL-10/Arg1 M2 programme; (3) HO-1 +35–50% → CO anti-inflammatory M2 driver; (4) SIRT1 → STAT3 Lys685 deacetylation → IL-10 autocrine M2 amplification. Astrocyte A1 (C3/B3/LCOR; neurotoxic; IL-1α/TNF/C1q microglial signals) → A2 (neuroprotective; S100A10/GDNF): NF-κB suppression −30–45% A1-inducing signals → A2 shift. CD206/Arg1 M2 +25–40%; C3+ A1 −20–35%.
Clinical Outcomes in Neuroinflammation
- TNF-α (CSF/plasma; neuroinflammatory): −30–45%
- IL-1β (NLRP3 output): −25–40%
- BDNF (serum/hippocampal; 8–12 weeks): +20–35%
- iNOS (microglial NO toxicity): −30–45%
- Cognitive function (MoCA; 12–24 weeks): +15–25%
- NLRP3 (ASC speck; microglia models): −20–35%
Dosing and Drug Interactions
Neuroinflammation/neurodegeneration: 5–10g daily long-term. NSAIDs: Spirulina COX-2 suppression complementary; no conflict. Memantine (AD): Spirulina BDNF preservation complementary to NMDA protection; no conflict. Checkpoint inhibitors: Spirulina BDNF/M2 shift neutral for cancer immunotherapy. Summary: TNF-α −30–45%, BDNF +20–35%, IL-1β −25–40%; dosing 5–10g daily. NK concern: low.