KYNA

Kynurenic acid (KYNA) is a neuroprotective metabolite produced in skeletal muscle during exercise when PGC-1α upregulates kynurenine aminotransferases (KATs) to convert circulating kynurenine into KYNA, a compound that—unlike its precursor—cannot readily cross the blood–brain barrier PMID 40818821PMID 39456173PMID 38249295. By sequestering kynurenine peripherally and antagonizing NMDA receptors, KYNA can mediate resilience to stress-induced depression PMID 40869331PMID 39456173PMID 38393277PMID 38249295. It also promotes adipose tissue browning via GPR35 signaling PMID 40869331.

• Receptor Antagonism: KYNA acts as an endogenous antagonist of excitatory amino acid receptors. Specifically, it blocks N-methyl-D-aspartate (NMDA) receptors, Kainate receptors (KARs), and α7 nicotinic acetylcholine receptors (α7nAChR). By inhibiting these receptors, KYNA modulates neurotransmission PMID 40869331PMID 38393277PMID 38249295PMID 34782555.
• GPR35 Activation: In peripheral tissues like adipose tissue and immune cells, KYNA binds to the G-protein-coupled receptor 35 (GPR35) which triggers anti-inflammatory responses PMID 40869331.
• Neuroprotection vs. Neurotoxicity: Within the kynurenine pathway, tryptophan is converted to kynurenine (KYN). KYN can then be metabolized into either the neurotoxic quinolinic acid (QUIN) or the neuroprotective KYNA. KYNA protects neurons by counteracting the excitotoxic and oxidative effects of QUIN, which overactivates NMDA receptors PMID 40869331PMID 38249295PMID 34782555.

KYNA is classified as an exerkine (specifically a myokine) because physical activity directly regulates the enzymes responsible for its production, altering its systemic levels to benefit multiple organs.

• KAT Upregulation via PGC-1α: Exercise activates PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) in skeletal muscle. This upregulation increases the expression of kynurenine aminotransferases (KATs), the enzymes that convert KYN into KYNA PMID 40818821PMID 40869331PMID 38249295.
• Detoxification Mechanism (Peripheral Sink): Unlike its precursor KYN, KYNA does not readily cross the blood–brain barrier (BBB). By converting peripheral KYN into KYNA within skeletal muscle, exercise effectively lowers the amount of KYN available to cross into the brain. This prevents the central accumulation of neurotoxic metabolites (like QUIN) generated from KYN in the brain, thereby protecting the brain from stress-induced damage PMID 39136551PMID 39456173PMID 35283168.
• Systemic Release: Plasma and sweat levels of KYNA increase immediately after acute exercise and endurance training, shifting the ratio of KYN/KYNA in favor of the protective KYNA PMID 38249295PMID 35283168.

• Depression and Stress Resilience: By preventing the accumulation of neurotoxic KYN metabolites in the brain, the exercise-induced shift toward peripheral KYNA mediates resilience to stress-induced depression PMID 40818821PMID 39136551, 2024; PMID 39456173.
• Neurodegenerative Diseases (NDs): KYNA has therapeutic potential for Huntington’s diseases due to its anti-inflammatory and anti-excitotoxic properties. It mitigates neuronal loss and neuroinflammation PMID 38249295PMID 35283168PMID 34782555.
• Metabolic Syndrome and Obesity: Through its interaction with GPR35 in adipose tissue, KYNA triggers the browning of white adipocytes and enhances lipid metabolism in mouse models. This mechanism helps regulate energy homeostasis and reduces inflammation associated with obesity PMID 40869331PMID 38249295.
• Cancer Cachexia: In cancer states, inflammation often drives the pathway toward neurotoxic metabolites that damage the neuromuscular junction. Thus, promoting the KYNA pathway via exercise may help preserve muscle mass and function in cachexia patients PMID 40869331.

1. Neurological and Psychiatric Disorders

• Memory, Mood, and Learning: Recent studies demonstrate that expanded KYNA signaling in the primate prefrontal cortex impairs working memory via NMDA and α7-nicotinic receptor blockade PMID 38915595. Chronic stress also increases KYNA, leading to depressive behaviors PMID 39658392. Conversely, reducing KYNA levels via steroid hormones like ADIOL has been shown to promote learning PMID 38092521.
• Neuroprotection: In contrast to its negative cognitive effects, KYNA exhibits neuroprotective properties. Higher cerebrospinal fluid concentrations of KYNA are associated with slower clinical progression in Alzheimer's disease PMID 37264981. In stroke, baseline KYNA levels may serve as biomarkers for early improvement following thrombolysis PMID 34637198. Furthermore, drugs like Memantine appear to exert efficacy partly by selectively increasing cortical KYNA PMID 39272996.
• Therapeutic Innovations: To overcome KYNA's poor blood-brain barrier permeability and potential for motor toxicity (ataxia), researchers are developing novel delivery systems and analogs. KYNA-loaded micelles have shown neuroprotection in Parkinson's disease models PMID 38779944. Additionally, the structural analog SZR-73 has been optimized to provide therapeutic neuromodulation without the motor toxicity associated with KYNA PMID 40643494. However, the timing of such treatments is critical, as brain KYNA synthesis is sensitive to circadian rhythms PMID 41573955.

2. Inflammatory and Immune-Mediated Diseases

• Arthritis: In rheumatoid arthritis and spondyloarthritis, KYNA analogs inhibit the production of pro-inflammatory mediators like TNF-α and calgranulins while upregulating the anti-inflammatory protein TSG-6 PMID 33897688PMID 41465233.
• Infection and Immunity: KYNA activates GPR35 to inhibit the NLRP3 inflammasome and reduce IL-1β secretion in severe pneumonia PMID 40106903. It also protects against mastitis by enhancing blood-milk barrier integrity PMID 34247099.
• Stem Cell Therapy: Pre-treating mesenchymal stem cells with KYNA and IFN-γ enhances their therapeutic efficacy in treating colonic fibrosis by upregulating IDO-1 signaling PMID 36076306.

3. Gastrointestinal and Metabolic Health

• Intestinal Health: KYNA protects against intestinal damage caused by chemotherapy PMID 33777681 and invasive Candida albicans infection PMID 35923391. In Crohn's disease, KYNA derived from the mesentery promotes the "browning" of adipose tissue, which helps regulate mesenteritis PMID 40623474.
• Metabolic Disorders: KYNA acts as a signaling molecule that can delay the onset of type 2 diabetes and promote energy expenditure by stimulating uncoupling protein (UCP) expression PMID 37424591. It also attenuates nonalcoholic fatty liver disease (NAFLD) via AMPK/autophagy signaling PMID 33283879.
• Bone Health: Exercise-induced production of KYNA in skeletal muscle has been shown to alleviate postmenopausal osteoporosis via the GPR35/NFκB pathway PMID 35846727.

4. Oncology

• Glioblastoma (GBM): KYNA levels are downregulated in GBM; administration of KYNA has been shown to remodel the tumor immune microenvironment, reversing T-cell exhaustion and reducing tumor burden PMID 41221633.
• Other Cancers: KYNA induces apoptosis in gastric cancer cells by suppressing AP-1 factors PMID 36615849 and exhibits cytotoxicity against melanoma cells PMID 37661337. The interaction between KYNA and the HCAR3 receptor is also under investigation as a target for cancer immunometabolic regulation PMID 40650047.