Xanthine is a naturally occurring purine base widely found in plants such as tea and cocoa, and Xanthine serves as a key intermediate in the purine metabolic pathway within living organisms[1-2]. Xanthine is primarily generated from guanine through deamination catalyzed by guanine deaminase or from hypoxanthine via oxidation catalyzed by Xanthine oxidoreductase (XOR), and is further metabolized to uric acid[3-4].
In vitro, treatment of 8-day-old Sprague-Dawley rat cerebellar granule neurons with Xanthine (100μM) combined with Xanthine oxidase (0.02U/ml) for 1 or 6 hours, Xanthine significantly reduced cell viability and induced atrophy of cell bodies and synaptic morphology[5]. Treatment of human umbilical vein endothelial cells (HUVECs) with Xanthine (3-100μM) for 15 minutes, Xanthine activated the platelet-activating factor pathway via Xanthine oxidase-derived hydrogen peroxide, leading to enhanced neutrophil-endothelial adhesion[6].
In vivo, intraperitoneal administration of Xanthine (500mg/kg) to C57BL/6J mice (every three days for 20 days), Xanthine induced hippocampus-dependent spatial memory deficits and a tendency toward anxiety-like behavior, while upregulating the expression of hemoglobin genes (such as Hba-a1 and HBA2) in hippocampal neurons, resulting in cognitive and behavioral abnormalities[7].
References:
[1] POMALES R, ELION GB, HITCHINGS GH. XANTHINE AS A PRECURSOR OF NUCLEIC ACID PURINES IN THE MOUSE. Biochim Biophys Acta. 1965 Mar 15;95:505-6.
[2] Kanemitsu H, Tamura A, Kirino T, et al. Xanthine and uric acid levels in rat brain following focal ischemia. J Neurochem. 1988 Dec;51(6):1882-5.
[3] Zhang A, Ai L. Xanthine negatively regulates c-MYC through the PI3K/AKT signaling pathway and inhibits the proliferation, invasion, and migration of breast cancer cells. Asia Pac J Clin Oncol. 2025 Feb;21(1):3-11.
[4] Fan KQ, Li YY, Wang HL, et al. Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior. Cell. 2019 Oct 31;179(4):864-879.e19.
[5] Fatokun AA, Stone TW, Smith RA. Hydrogen peroxide mediates damage by xanthine and xanthine oxidase in cerebellar granule neuronal cultures. Neurosci Lett. 2007 Apr 6;416(1):34-8.
[6] Ichikawa H, Wolf RE, Aw TY, et al. Exogenous xanthine promotes neutrophil adherence to cultured endothelial cells. Am J Physiol. 1997 Aug;273(2 Pt 1):G342-7.
[7] Kambe J, Miyata S, Li C, et al. Xanthine-induced deficits in hippocampal behavior and abnormal expression of hemoglobin genes. Behav Brain Res. 2023 Jul 9;449:114476.