The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis

Abstract

Progressive multiple sclerosis (MS) is a chronic disease with a unique pattern, which is histologically classified into the subpial type 3 lesions in the autopsy. The lesion is also homologous to that of cuprizone (CPZ) toxin-induced animal models of demyelination. Aberration of the tryptophan (TRP)-kynurenine (KYN) metabolic system has been observed in patients with MS; nevertheless, the KYN metabolite profile of progressive MS remains inconclusive. In this study, C57Bl/6J male mice were treated with 0.2% CPZ toxin for 5 weeks and then underwent 4 weeks of recovery. We measured the levels of serotonin, TRP, and KYN metabolites in the plasma and the brain samples of mice at weeks 1, 3, and 5 of demyelination, and at weeks 7 and 9 of remyelination periods by ultra-high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) after body weight measurement and immunohistochemical analysis to confirm the development of demyelination. The UHPLC-MS/MS measurements demonstrated a significant reduction of kynurenic acid, 3-hydoxykynurenine (3-HK), and xanthurenic acid in the plasma and a significant reduction of 3-HK, and anthranilic acid in the brain samples at week 5. Here, we show the profile of KYN metabolites in the CPZ-induced mouse model of demyelination. Thus, the KYN metabolite profile potentially serves as a biomarker of progressive MS and thus opens a new path toward planning personalized treatment, which is frequently obscured with immunologic components in MS deterioration.

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain

“…The balance of these KYNs affects the CNS and the immune system, and its dysregulation is linked to neuropsychiatric disorders [ 38 , 39 , 40 , 145 , 146 , 147 ]. Neurotoxic and neuroprotective branches of KYNs, the equilibrium of which is critical for maintaining homeostasis and function in the CNS, have been implicated in its degradation [ 47 , 48 , 49 , 148 , 149 ]. Conversely, KYN metabolites demonstrate an extensive array of bioactive characteristics, including but not limited to immunomodulating, oxidant, antioxidant, anti-inflammatory, and neurotoxin actions [ 150 , 151 , 152 ].…”

“…The maintenance of homeostasis and function in the CNS relies heavily on the equilibrium between various metabolic branches. Consequently, any disruption in this balance can result in the development of pathological conditions [ 47 , 48 , 49 ]. However, this balance can be disturbed by various factors, resulting in the accumulation of neurotoxic KYNs and the depletion of neuroprotective KYNs in the CNS [ 50 , 51 , 52 ].…”

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models

“…The findings suggest that in a preclinical model, this combined treatment can effectively reduce the severity of MS symptoms and improve overall outcomes, potentially leading to the development of novel MS therapeutic strategies [35]. Thus, it is evident that the application of preclinical models has been instrumental in propelling research on MS forward [36]. These investigations have not only deepened our understanding of the intricate pathophysiology implicated in the condition, but have also been key in identifying potential biomarkers [37,38].…”

New insight on microglia activation in neurodegenerative diseases and therapeutics

“…The activated microglia engulf the myelin sheath, causing extensive and severe axonal damage and microgliosis. Recent studies have found that the Tryptophan-Kynurenine Metabolic System is inhibited in animal models of CPZ (Polyák et al, 2023). Dysregulation of TRP-KYN metabolism is strongly associated with the neurodegenerative process, mainly through microglia activation.…”