Quinolinic acid induces neuritogenesis in SH‐SY5Y neuroblastoma cells independently of NMDA receptor activation |
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| Authors: | Juan‐Manuel Hernandez‐Martinez Caroline M Forrest L Gail Darlington Robert A Smith Trevor W Stone |
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| Affiliation: | 1. Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK;2. Internal Medicine, Ashtead Hospital, Ashtead, UK |
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| Abstract: | Glutamate and nicotinamide adenine dinucleotide (NAD+) have been implicated in neuronal development and several types of cancer. The kynurenine pathway of tryptophan metabolism includes quinolinic acid (QA) which is both a selective agonist at N‐methyl‐D‐aspartate (NMDA) receptors and also a precursor for the formation of NAD+. The effect of QA on cell survival and differentiation has therefore been examined on SH‐SY5Y human neuroblastoma cells. Retinoic acid (RA, 10 μm ) induced differentiation of SH‐SY5Y cells into a neuronal phenotype showing neurite growth. QA (50–150 nm ) also caused a concentration‐dependent increase in the neurite/soma ratio, indicating differentiation. Both RA and QA increased expression of the neuronal marker β3‐tubulin in whole‐cell homogenates and in the neuritic fraction assessed using a neurite outgrowth assay. Expression of the neuronal proliferation marker doublecortin revealed that, unlike RA, QA did not decrease the number of mitotic cells. QA‐induced neuritogenesis coincided with an increase in the generation of reactive oxygen species. Neuritogenesis was prevented by diphenylene‐iodonium (an inhibitor of NADPH oxidase) and superoxide dismutase, supporting the involvement of reactive oxygen species. NMDA itself did not promote neuritogenesis and the NMDA antagonist dizocilpine (MK‐801) did not prevent quinolinate‐induced neuritogenesis, indicating that the effects of QA were independent of NMDA receptors. Nicotinamide caused a significant increase in the neurite/soma ratio and the expression of β3‐tubulin in the neuritic fraction. Taken together, these results suggest that QA induces neuritogenesis by promoting oxidizing conditions and affecting the availability of NAD+, independently of NMDA receptors. |
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| Keywords: | differentiation glutamate kynurenines
NAD
+
nicotinamide |
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