Neuroinflammation of Microglial Regulation in Alzheimer’s Disease: Therapeutic Approaches
Abstract
:1. Introduction
2. Microglia’s Role in AD
2.1. Main Physiological Functions of Microglia
2.2. Microglial Activation-Mediated Neuroinflammation in AD
3. The Critical Role of Energy Metabolic Disorder of Microglia between Microglial Activation-Mediated Neuroinflammation and AD
4. Anti-Inflammatory Drugs for the Treatment of AD
4.1. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
4.2. TLR4 Antagonists
4.3. p38 Mitogen-Activated Protein Kinase (p38 MAPK) Antagonists
4.4. Microglia Regulators
4.5. Chinese Herbal Polysaccharides
4.6. Other Anti-Inflammatory Drugs
5. Discussion and Outlook
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Agent | Type | CADRO Target | Mechanism of Action | Clinical Trial NCT# |
---|---|---|---|---|
Masitinib (Phase 3) | small molecule | Inflammation | Tyrosine kinase inhibitor exhibits neuroprotection via inhibition of mast cell and microglia/macrophage activity | NCT05564169 |
NE3107 (Phase 3) | small molecule | Inflammation | Beta-androstenetriol with anti-inflammatory and insulin signaling effects via ERK 1 and 2 | NCT04669028 |
Baricitinib (Phase 2) | small molecule | Inflammation | Janus kinase (JAK) inhibitor | NCT05189106 |
Dasatinib + Quercetin (Phase 2) | small molecule | Inflammation | Dasatinib induces apoptosis in senescent cells to allow their removal; quercetin is a flavonoid | NCT04063124 |
NCT04685590 | ||||
NCT04785300 | ||||
NCT05422885 | ||||
L-Serine (Phase 2) | small molecule | Inflammation | Naturally occurring dietary amino acid; inhibits toxic misfolding | NCT03062449 |
Lenalidomide (Phase 2) | small molecule | Inflammation | Immunomodulator | NCT04032626 |
Montelukast (Phase 2) | small molecule | Inflammation | Leukotriene receptor antagonist (LTRA); anti-inflammatory effects | NCT03402503 |
Senicapoc (Phase 2) | small molecule | Inflammation | Calcium-activated potassium channel inhibitor | NCT04804241 |
Valacyclovir (Phase 2) | small molecule | Inflammation | Anti-viral against HSV-1 and −2; reduces vira-related “seeding” of ABP deposition | NCT03282916 |
Salsalate (Phase 1) | small molecule | Inflammation | Non-steroidal anti-inflammatory (NSAID) | NCT03277573 |
Emtricitabine (Phase 1) | small molecule | Inflammation | Nucleoside reverse transcriptase inhibitor (NRTI) | NCT04500847 |
Drug Name | Chemical Structures | Category | Compound Effects |
---|---|---|---|
Masitinib | Tyrosine kinase inhibitor | Downregulated proinflammatory cytokines. Induced neuroprotection [104]. | |
NE3107 | NF-κB inhibitor | Decreased activated microglia, Aβ [105]. | |
Baricitinib | JAK inhibitor | Blocked intracellular delivery of cytokines via JAK-STAT [106]. | |
Dasatinib + Quercetin | Tyrosine kinase inhibitor | Alleviated neurodegeneration in AD [107]. | |
PI3K/Akt inhibitor | |||
L-Serine | mTOR inhibitor | Autophagic clearance of Aβ [108]. | |
Lenalidomide | Immunomodulator | Decreased the expression of TNFα, IL-6, IL-8. Increased the expression of anti-inflammatory cytokines [109]. | |
Montelukast | Cytochrome P-450 Enzyme Inducers | Increased expression of P450 enzymes [110]. | |
Senicapoc | KCa3.1 inhibitor | Regulated microglia polarization [111]. | |
Valacyclovir | Anti-virus | Reduced accumulation of Aβ and p-tau [112]. | |
Salsalate | NASID | Inhibited inflammatory mediators [113]. | |
Emtricitabine | Anti-virus | Suppressed neuroinflammation [114]. |
Drug Name | Chemical Structures | Category | Compound Effects |
---|---|---|---|
CHF5074 | Improved cognition. Reduced brain inflammation [115]. | ||
Indomethacin | Cox-2 inhibitor | Inhibited inflammatory mediators released from microglia [116]. | |
Furosemide | Inhibited protein expression of COX-2,iNOS. | ||
Azeliragon | Mediated the JAK1/STAT3/NF-κB/IRF3 pathway [117]. | ||
TAK242 | TLR4 antagonists | Reduced Aβ deposition [118]. | |
Gx-50 | Suppressed of TLR4-mediated NF-κB/MAPK signaling [119]. | ||
Naloxone | Inhibited reactive oxygen species production [120]. | ||
VX745 | p38-MAPK antagonists | Reduced IL-1β protein levels in the hippocampus [121]. | |
PRZ-18002 | Degraded phosphorylated p38 MAPK (p-p38) [122]. | ||
Alleviated microglial activation and Aβ deposition [122]. | |||
Urolithin | Reduced NO levels and suppressed pro-inflammatory genes [123]. | ||
TSG | Microglia regulators | Inhibited PKM2 to adjust microglia polarization [124]. | |
Resveratrol | Adjusted microglia polarization [124,125,126]. | ||
Cromolyn | Induced neuroprotective microglial activation [127]. | ||
CIAC001 | PKM2 inhibitor | Ameliorated morphine-induced addiction through anti-neuroinflammation [128]. | |
Benserazide | Inhibited PKM2, thereby blocking aerobic glycolysis and modulating OXPHOS [129]. | ||
Rutin | Promoted a metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS [130]. | ||
Rapamycin | mTOR inhibitor | Activated mitophagy and alleviated cognitive impairment [131]. | |
Salidroside | Inhibited Aβ deposit. Anti-inflammation [132]. | ||
GV-971 | Chinese herbal polysaccharides | Remodeled gut microbiota to inhibit AD progression [133]. | |
Ganoderma lucidum polysaccharides | / | Reduced Aβ levels and tau protein hyperphosphorylation [134]. | |
Astragalus polysaccharides | / | Reduced astrocytic and microglial activation [135]. | |
Dendrobium orchid polysaccharide | / | Inhibited oxidative stress [136]. | |
Astragalus polysaccharide | / | Decreased the phosphorylation of p38 MAPK [137]. | |
Tacrine | AChE inhibitor | Inhibited acetylcholinesterase activity [138]. | |
The derivative of tacrine | |||
Donepezil | |||
Dapansutrile | NLRP3 Inhibitor | Inhibited the associated NLRP3 inflammatory response [120]. | |
MC950 | Reduced Aβ deposition and associated neurotoxicity [139]. | ||
JC124 | Reduced CAA, microgliosis and oxidative stress [140]. | ||
CY-09 | Inhibited the associated NLRP3 inflammatory response [141]. | ||
Inzomelid | Inhibited the associated NLRP3 inflammatory response [142]. |
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Chen, H.; Zeng, Y.; Wang, D.; Li, Y.; Xing, J.; Zeng, Y.; Liu, Z.; Zhou, X.; Fan, H. Neuroinflammation of Microglial Regulation in Alzheimer’s Disease: Therapeutic Approaches. Molecules 2024, 29, 1478. https://doi.org/10.3390/molecules29071478
Chen H, Zeng Y, Wang D, Li Y, Xing J, Zeng Y, Liu Z, Zhou X, Fan H. Neuroinflammation of Microglial Regulation in Alzheimer’s Disease: Therapeutic Approaches. Molecules. 2024; 29(7):1478. https://doi.org/10.3390/molecules29071478
Chicago/Turabian StyleChen, Haiyun, Yuhan Zeng, Dan Wang, Yichen Li, Jieyu Xing, Yuejia Zeng, Zheng Liu, Xinhua Zhou, and Hui Fan. 2024. "Neuroinflammation of Microglial Regulation in Alzheimer’s Disease: Therapeutic Approaches" Molecules 29, no. 7: 1478. https://doi.org/10.3390/molecules29071478