Xanthine oxidase and phytic acid

[ironjustice]

Xanthine oxidase mediates axonal and myelin loss in a murine model of multiple sclerosis
Josephe Archie Honorat 1, Makoto Kinoshita, Tatsusada Okuno, Kazushiro Takata, Toru Koda, Satoru Tada, Takashi Shirakura, Harutoshi Fujimura, Hideki Mochizuki, Saburo Sakoda, Yuji Nakatsuji
PLoS One. 2013 Aug 8;8(8):e71329. doi: 10.1371/journal.pone.0071329. eCollection 2013.

PMID: 23951137 PMCID: PMC3738596 DOI: 10.1371/journal.pone.0071329
Abstract
Objectives: Oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS). Though reactive oxygen species (ROS) are produced by various mechanisms, xanthine oxidase (XO) is a major enzyme generating ROS in the context of inflammation. The objectives of this study were to investigate the involvement of XO in the pathogenesis of MS and to develop a potent new therapy for MS based on the inhibition of ROS.

Methods: XO were assessed in a model of MS: experimental autoimmune encephalomyelitis (EAE). The contribution of XO-generated ROS to the pathogenesis of EAE was assessed by treating EAE mice with a novel XO inhibitor, febuxostat. The efficacy of febuxostat was also examined in in vitro studies.

Results: We showed for the first time that the expression and the activity of XO were increased dramatically within the central nervous system of EAE mice as compared to naïve mice. Furthermore, prophylactic administration of febuxostat, a XO inhibitor, markedly reduced the clinical signs of EAE. Both in vivo and in vitro studies showed infiltrating macrophages and microglia as the major sources of excess XO production, and febuxostat significantly suppressed ROS generation from these cells. Inflammatory cellular infiltration and glial activation in the spinal cord of EAE mice were inhibited by the treatment with febuxostat. Importantly, therapeutic efficacy was observed not only in mice with relapsing-remitting EAE but also in mice with secondary progressive EAE by preventing axonal loss and demyelination.

Conclusion: These results highlight the implication of XO in EAE pathogenesis and suggest XO as a target for MS treatment and febuxostat as a promising therapeutic option for MS neuropathology.

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Inhibition of xanthine oxidase by phytic acid and its antioxidative action
Sanae Muraoka 1, Toshiaki Miura
Life Sci. 2004 Feb 13;74(13):1691-700. doi: 10.1016/j.lfs.2003.09.040.

PMID: 14738912 DOI: 10.1016/j.lfs.2003.09.040
Abstract
We examined if phytic acid inhibits the enzymatic superoxide source xanthine oxidase (XO). Half inhibition of XO by phytic acid (IC50) was about 30 mM in the formation of uric acid from xanthine, but generation of the superoxide was greatly affected by phytic acid; the IC50 was about 6 mM, indicating that the superoxide generating domain of XO is more sensitive to phytic acid. The XO activity in intestinal homogenate was also inhibited by phytic acid. However, it was not observed with intestinal homogenate that superoxide generation was more sensitive to phytic acid compared with the formation of uric acid as observed with XO from butter milk. XO-induced superoxide-dependent lipid peroxidation was inhibited by phytic acid, but not by myo-inositol. Reduction of ADP-Fe3+ caused by XO was inhibited by superoxide dismutase, but not phytic acid. The results suggest that phytic acid interferes with the formation of ADP-iron-oxygen complexes that initiate lipid peroxidation. Both phytic acid and myo-inositol inhibited XO-induced superoxide-dependent DNA damage. Mannitol inhibited the DNA strand break. Myo-inositol may act as a hydroxyl radical scavenger. The antioxidative action of phytic acid may be due to not only inhibiting XO, but also preventing formation of ADP-iron-oxygen complexes.

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