Perspectives in Pharmacology Altered Uric Acid Levels and Disease States

Altered serum uric acid concentrations, both above and below normal levels, have been linked to a number of disease states. An abnormally high uric acid level has been correlated with gout, hypertension, cardiovascular disease, and renal disease, whereas a reduced uric acid concentration has been linked to multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and optic neuritis. Historically, uric acid has been considered a marker of these disease states. Recent studies, however, have provided evidence that uric acid may actually play a role in the development or progression of such diseases. As a result, the manipulation of uric acid concentrations is now either included in, or being investigated for, the treatment of a variety of disease states. Uric acid (UA; 7,9-dihydro-1H-purine-2,6,8(3H)-trione) has been implicated as a risk factor and cause of numerous disease states. Some disease states, such as gout, hypertension, and cardiovascular disease, have been shown to result when UA levels in the blood are too high. Other conditions, such as neurodegenerative diseases, may be caused by reduced serum UA levels. Consequently, the manipulation of serum UA levels has become a popular strategy in the treatment of a variety of diseases (Table 1). One approach in the treatment of gout, for example, is to reduce the overall serum UA concentration. This is either accomplished through dietary and lifestyle changes or through treatment with UA reducing drugs (Emmerson, 1996; Choi et al., 2005). Alternatively, increasing UA levels has been proposed as a therapy for the treatment of neurodegenerative diseases, such as multiple sclerosis (MS), and for the treatment of both spinal cord injury and stroke because of the neuroprotective properties of UA. UA has been found to both prevent and alleviate the symptoms of experimental allergic encephalomyelitis (EAE), the animal model of MS, in mice (Hooper et al., 2000). The administration of inosine, a UA precursor, has been shown to have a similar therapeutic effect in the treatment of EAE (Scott et al., 2002). Some success was reported using inosine to treat MS patients as a method of raising the serum UA concentration (Spitsin et al., 2001a). Likewise, both UA and inosine have recently been implicated as possible treatments following spinal cord injury. Our laboratory has recently reported that the administration of UA after a simulated spinal cord injury in vitro resulted in a decrease in secondary neuronal damage (Du et al., 2007). This result is in agreement with in vivo studies by Hooper and colleagues that showed that UA protects when administered before spinal cord injury (Scott et al., 2005). A related result by Ju and colleagues found that inosine also protects spinal cord neurons from secondary damage (Liu et al., 2006). The adjustment of UA levels as a treatment strategy has proven to be successful for a number of disorders; however, because disease states result from both high and low UA levels, the manipulation of UA levels above or below normal levels could possibly lead to unwanted side effects. Ideally, decreasing UA levels to treat a disease caused by an elevated UA level should not leave a patient more susceptible to the development of a condition that may result from a reduced UA level. This review will outline the variety of disease states that have been shown to, or are believed to, result from This work was funded as part of paid consulting work for Savient Pharmaceuticals (East Brunswick, NJ) (to B.L.F.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.129031. ABBREVIATIONS: UA, uric acid; MS, multiple sclerosis; EAE, experimental allergic encephalomyelitis; NO, nitric oxide; NOS, NO synthase; PD, Parkinson’s disease; AD, Alzheimer’s disease; URAT1, urate transporter 1; RAS, renin angiotensin system; MRP4, multidrug resistance protein 4; OAT, organic ion transporter; BBB, blood-brain barrier. 0022-3565/08/3241-1–7$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 324, No. 1 Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics 129031/3280353 JPET 324:1–7, 2008 Printed in U.S.A. 1 at A PE T Jornals on A ril 9, 2017 jpet.asjournals.org D ow nladed from altered serum UA levels. It will also briefly summarize some of the mechanisms by which altered UA levels can lead to such conditions.