Tryptophan and Kynurenine Pathway Metabolites in Animal Models of Retinal and Optic Nerve Damage: Different Dynamics of Changes

Abstract

Kynurenines, products of tryptophan (TRP) metabolism, display neurotoxic (e.g., 3-hydroxykynurenine; 3-HK), or neuroprotective (e.g., kynurenic acid; KYNA) properties. Imbalance between the enzymes constituting the kynurenine pathway (KP) plays a role in several disease, including neurodegeneration. In this study, we track changes in concentrations of tryptophan and its selected metabolites after damage to retinal ganglion cells and link this data with expression of KP enzymes. Brown-Norway rats were subjected to intravitreal N-methyl-D-aspartate (NMDA) injection or partial optic nerve crush (PONC). Retinas were collected 2 and 7 days after the completion of PONC or NMDA injection. Concentrations of TRP, kynurenine (KYN), and KYNA were determined by high performance liquid chromatography (HPLC). Data on gene expression in the rat retina were extracted from GEO, public microarray experiments database. Two days after NMDA injection concentration of TRP decreased, while KYN and KYNA increased. At day 7 compared to day 2 decrease of KYN, KYNA and further reduction of TRP concentration were observed, but on day 7 KYN concentration was still elevated when compared to controls. At day 2 and 7 after NMDA injection no statistically significant alterations of 3-HK were observed. TRP and 3-HK concentration was higher in PONC group than in controls. However, both KYN and KYNA were lower. At day seven concentration of TRP, 3-HK, and KYN was higher, whereas concentration of KYNA declined. In vivo experiments showed that retinal damage or optic nerve lesion affect TRP metabolism via KP. However, the pattern of changes in metabolite concentrations was different depending on the model. In particular, in PONC KYNA and KYN levels were decreased and 3-HK elevated. These observations correspond with data on expression of genes encoding KP enzymes assessed after optic nerve crush or transection. After intraorbital optic nerve crush downregulation of KyatI and KyatIII between 24 h and 3 days after procedure was observed. Kmo expression was transiently upregulated (12 h after the procedures). After intraorbital optic nerve transsection (IONT) Kmo expression was upregulated after 48 h and 7 days, KyatI and KyatIII were downregulated after 12, 48 h, 7 days and upregulated after 15 days. Collected data point to the conclusion that development of therapeutic strategies targeting the KP could be beneficial in diseases involving retinal neurodegeneration.

Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma

“…S1 ). These metabolites induce exictotoxicity and cause neuronal and retinal ganglion cell death 64 , 65 . Previous studies have also reported elevated levels of ATP and glutamate in glaucoma 38 , 66 .…”

Metabolomics profiles associated with diabetic retinopathy in type 2 diabetes patients

“…Of note, tryptophan was metabolized to kynurenine, and its concentration was decreased in the abovementioned models. The concentration of kynurenine, the product of tryptophan metabolism, was reciprocally increased [ 24 ]. It was reported that a higher IDO expression was observed in NPDR patients than in NDR patients; interestingly, an even higher IDO expression was observed in PDR versus NPDR patients.…”

Tryptophan Pathway Abnormalities in a Murine Model of Hereditary Glaucoma

“…Our previous results also demonstrated changes in retinal KYNA in two surgical models of glaucoma. A complex response was noted after NMDA administration (a transient increase 2 days after NMDA injection and then a decrease) and a massive decrease of retinal KYNA concentration due to partial optic nerve crush [ 14 ]. The decrease in KYNA concentration observed in this study seems to be an effect of KP failure.…”

“…Microglia activation was previously shown to be an early event in the course of glaucomatous pathology in DBA/2J mice and to correlate with the severity of neurodegeneration in these mice [ 44 ]. We have also recently shown that KMO is overexpressed in two animal models of glaucoma: optic nerve crush and NMDA-induced RGC loss [ 14 ]. Interestingly, the dynamics of changes differed in these two animal models (peak expression 12 h after crush and 48 h after intravitreal NMDA administration).…”

“…Retinal KYNA levels were shown to be elevated in response to RGC damage [ 13 ]. As we recently have shown, the dynamics of KP alteration due to RGC damage is different depending on the nature of the insult (or animal model of RGC loss used) [ 14 ]. Importantly, recent results suggest that manipulation in KP enzymes activity may exert neuroprotective effects on RGC [ 15 ].…”