title: The neuroprotector kynurenic acid increases neuronal cell survival through neprilysin induction.
abstract: Kynurenic acid (KYNA), one of the main product of the kynurenine pathway originating from tryptophan, is considered to be neuroprotective. Dysregulation of KYNA activity is thought to be involved in neurodegenerative diseases, the physiopathology of which evokes excitotoxicity, oxidative stress and/or protein aggregation. The neuroprotective effect of KYNA is generally attributed to its antagonistic action on NMDA receptors. However, this single target action appears insufficient to support KYNA beneficial effects against complex neurodegenerative processes including neuroinflammation, β-amyloid peptide (Aβ) toxicity and apoptosis. Novel insights are therefore required to elucidate KYNA neuroprotective mechanisms. Here, we combined cellular, biochemical, molecular and pharmacological approaches to demonstrate that low micromolar concentrations of KYNA strongly induce neprilysin (NEP) gene expression, protein level and enzymatic activity increase in human neuroblastoma SH-SY5Y cells. Furthermore, our studies revealed that KYNA exerts a protective effect on SH-SY5Y cells by increasing their viability through a mechanism independent from NMDA receptors. Interestingly, KYNA also induced NEP activity and neuroprotection in mouse cortical neuron cultures the viability of which was more promoted than SH-SY5Y cell survival under KYNA treatment. KYNA-evoked neuroprotection disappeared in the presence of thiorphan, an inhibitor of NEP activity. NEP is a well characterized metallopeptidase whose deregulation leads to cerebral Aβ accumulation and neuronal death in Alzheimer's disease. Therefore, our results suggest that a part of the neuroprotective role of KYNA may depend on its ability to induce the expression and/or activity of the amyloid-degrading enzyme NEP in nerve cells.
authors: Biopathologie de Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Université de Strasbourg, Faculté de Médecine, 11 rue Humann, 67000 Strasbourg, France.
authors: Christian
authors: C
authors: Klein
authors: Christine
authors: C
authors: Patte-Mensah
authors: Omar
authors: O
authors: Taleb
authors: Jean-Jacques
authors: JJ
authors: Bourguignon
authors: Martine
authors: M
authors: Schmitt
authors: Frédéric
authors: F
authors: Bihel
authors: Michel
authors: M
authors: Maitre
authors: Ayikoe G
authors: AG
authors: Mensah-Nyagan
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D061251:Primary Cell Culture; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015244:Thiorphan / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D015244:Thiorphan; D015260:Neprilysin; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; C066192:5,7-dichlorokynurenic acid