GPR35 Agonists for Neurodegeneration
Introduction <table class="infobox infobox-therapeutic">Target </td>Drug Class </td>Endogenous Ligand </td>Signaling </td>
GPR35 is a G-protein coupled receptor that serves as the receptor for kynurenic acid (KYNA), a neuroactive metabolite of the tryptophan degradation pathway. GPR35 is widely expressed in the brain, particularly in microglia and neurons, where it mediates the neuroprotective effects of kynurenic acid. This receptor has emerged as a promising target for neurodegenerative disease therapy due to its roles in neuroinflammation, excitotoxicity, and oxidative stress. [@kl2018]
GPR35 Biology GPR35 is encoded by the [GPR35](/genes/gpr35) gene. Key features include:
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GPR35 Agonists for Neurodegeneration
Introduction <table class="infobox infobox-therapeutic">Target </td>Drug Class </td>Endogenous Ligand </td>Signaling </td>
GPR35 is a G-protein coupled receptor that serves as the receptor for kynurenic acid (KYNA), a neuroactive metabolite of the tryptophan degradation pathway. GPR35 is widely expressed in the brain, particularly in microglia and neurons, where it mediates the neuroprotective effects of kynurenic acid. This receptor has emerged as a promising target for neurodegenerative disease therapy due to its roles in neuroinflammation, excitotoxicity, and oxidative stress. [@kl2018]
GPR35 Biology GPR35 is encoded by the [GPR35](/genes/gpr35) gene. Key features include:
Primary Endogenous Ligand : Kynurenic acid (KYNA)Gi-coupled : Inhibits adenylate cyclase, reduces cAMPGq-coupled : Activates PLCβ in some contextsHigh Expression : Microglia, astrocytes, neuronsBrain Distribution : Cortex, hippocampus, basal ganglia, cerebellumGPR35 acts as a sensor of kynurenic acid levels in the brain, which increases during inflammation and neurodegeneration. The receptor mediates most of the neuroprotective effects of kynurenic acid. [@wl2019]
Mechanism of Action GPR35 agonists work through anti-inflammatory and neuroprotective signaling:
Mermaid diagram (expand to render)
Key Mechanisms
Anti-inflammatory Effects : GPR35 activation reduces pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6) in microglia through cAMP-dependent signaling. [@wl2019]Excitotoxicity Reduction : GPR35-mediated signaling reduces NMDA receptor overactivation, protecting against glutamate-induced excitotoxicity.Antioxidant Effects : Activation promotes Nrf2 pathway activation and reduces oxidative stress.Microglial Polarization : Shifts microglia from pro-inflammatory (M1) to neuroprotective (M2) phenotype.
Therapeutic Potential
Alzheimer's Disease GPR35 agonists may benefit AD through:
Reduction of amyloid-induced neuroinflammation
Protection against excitotoxicity
Support of cognitive function
Modulation of kynurenine pathway
Parkinson's Disease GPR35 is particularly relevant for PD:
High expression in substantia nigra
Protection of dopaminergic neurons
Reduction of microglial activation in basal ganglia
Potential to slow disease progression
Other Applications
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Huntington's Disease](/diseases/huntingtons-disease)
Stroke
Epilepsy
Drug Development GPR35 agonists are in various stages of development:
Drug Properties
Research Challenges
Kynurenic acid has limited BBB penetration
Synthetic analogs need optimization
Receptor desensitization with chronic use
Species differences in pharmacology
References
[GPR35: the kynurenic acid receptor in neuroprotection. Mol Neurobiol (2018)](https://pubmed.ncbi.nlm.nih.gov/29766434/)
[Wang J, et al. GPR35 activation reduces neuroinflammation in Parkinson's models. J Neuroinflammation (2019)](https://pubmed.ncbi.nlm.nih.gov/31672162/)
[Hernandez M, et al. Targeting GPR35 for Alzheimer's disease therapy. Pharmacol Res (2020)](https://pubmed.ncbi.nlm.nih.gov/32278543/)
Related Pages
[Neuroinflammation Modulation](/therapeutics/neuroinflammation-modulation-therapies)
[Kynurenine Pathway](/mechanisms/kynurenine-pathway)
[Microglial Modulation](/therapeutics/microglial-modulation-therapy-neurodegeneration)
[GPR35 Gene](/genes/gpr35)
From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
[Nutrient-Sensing Epigenetic Circuit Reactivation](/hypothesis/h-4bb7fd8c) — <span style="color:#81c784;font-weight:600">0.79</span> · Target: SIRT1
[CYP46A1 Overexpression Gene Therapy](/hypothesis/h-2600483e) — <span style="color:#81c784;font-weight:600">0.79</span> · Target: CYP46A1
[Circadian Glymphatic Entrainment via Targeted Orexin Receptor Modulation](/hypothesis/h-9e9fee95) — <span style="color:#81c784;font-weight:600">0.77</span> · Target: HCRTR1/HCRTR2
[Selective Acid Sphingomyelinase Modulation Therapy](/hypothesis/h-de0d4364) — <span style="color:#81c784;font-weight:600">0.77</span> · Target: SMPD1
[Membrane Cholesterol Gradient Modulators](/hypothesis/h-9d29bfe5) — <span style="color:#81c784;font-weight:600">0.76</span> · Target: ABCA1/LDLR/SREBF2
[Microbial Inflammasome Priming Prevention](/hypothesis/h-e7e1f943) — <span style="color:#81c784;font-weight:600">0.76</span> · Target: NLRP3, CASP1, IL1B, PYCARD
[Blood-Brain Barrier SPM Shuttle System](/hypothesis/h-959a4677) — <span style="color:#81c784;font-weight:600">0.75</span> · Target: TFRC
[Purinergic Signaling Polarization Control](/hypothesis/h-0758b337) — <span style="color:#81c784;font-weight:600">0.74</span> · Target: P2RY1 and P2RX7
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