Miquel Martorell*, Xavier Lucas, Pedro Alarcón-Zapata, Xavier Capó, Maria Magdalena Quetglas-Llabrés, Silvia Tejada and Antoni Sureda Pages 367 - 382 ( 16 )
Mental disorders comprise diverse human pathologies, including depression, bipolar affective disorder, schizophrenia, and dementia that affect millions of people around the world. The causes of mental disorders are unclear, but growing evidence suggests that oxidative stress and the purine/adenosine system play a key role in their development and progression. Xanthine oxidase (XO) is a flavoprotein enzyme essential for the catalysis of the oxidative hydroxylation of purines -hypoxanthine and xanthine- to generate uric acid. As a consequence of the oxidative reaction of XO, reactive oxygen species (ROS) such as superoxide and hydrogen peroxide are produced and, further, contribute to the pathogenesis of mental disorders. Altered XO activity has been associated with free radical-mediated neurotoxicity inducing cell damage and inflammation. Diverse studies reported a direct association between an increased activity of XO and diverse mental diseases including depression or schizophrenia. Small-molecule inhibitors, such as the well-known allopurinol, and dietary flavonoids, can modulate the XO activity and subsequent ROS production. In the present work, we review the available literature on XO inhibition by small molecules and their potential therapeutic application in mental disorders. In addition, we discuss the chemistry and molecular mechanism of XO inhibitors, as well as the use of structure-based and computational methods to design specific inhibitors with the capability of modulating XO activity.
Allopurinol, free radicals, xanthine oxidase, enzyme inhibition, natural products, inflammation.
Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepcion, 4070386 Concepcion, Roche Pharma Research and Early Development, Roche Innovation Center, Basel CH-4070, Clinical Biochemistry and Immunology Department, Faculty of Pharmacy, University of Concepcion, 4070386 Concepcion, Research Group in Community Nutrition and Oxidative Stress, University of Balearic Islands & Health Research Institute of the Balearic Islands (IdISBa), E-07122, Palma, Balearic Islands, Laboratory of Neurophysiology, Department of Biology, University of Balearic Islands & Health Research Institute of the Balearic Islands (IdISBa), E-07122, Palma, Balearic Islands, Laboratory of Neurophysiology, Department of Biology, University of Balearic Islands & Health Research Institute of the Balearic Islands (IdISBa), E-07122, Palma, Balearic Islands, Research Group in Community Nutrition and Oxidative Stress, University of Balearic Islands & Health Research Institute of the Balearic Islands (IdISBa), E-07122, Palma, Balearic Islands