Pathway for ascertaining the role of uric acid in neurodegenerative diseases

Abstract

Uric acid is the end product of purine metabolism. Elevated serum urate level, a condition known as hyperuricemia, is a cardiovascular disease risk factor. [1][2][3] Low urate level, a condition known as hypouricemia, is a risk factor for developing neurodegenerative diseases. 4 The upper normal uric acid levels could range between 6 and 6.8 mg/dL in healthy adults with normal kidney function. Maintaining normal urate levels provides significant antioxidant and neuroprotective effects.High urate levels above saturation threshold (6.8 mg/dL) are considered a pro-inflammatory condition, leading to increased oxidative stress, increased renin-angiotensin levels, activated aldosterone system, increased systemic vascular resistance, and reduced renal blood flow, and consequently hypertension and worsening kidney function. 5 Low serum urate levels are a risk factor for developing neurodegenerative diseases (Figure 1). Although the exact mechanism that uric acid exerts as a neuroprotective biochemical is not elucidated, it is believed that uric acid levels are scavengers of free radicals, superoxide, and hydrogen peroxide. 6 Urate levels are responsible for 55% of free radicals' scavenging capacity in the human body. 6,7 Thus, low uric acid levels could augment the risk of oxidative stress, increasing the accumulation of reactive oxygen species, which may permeate the effect of tau protein on neuro entanglement, leading to a decline in cognitive function and preclinical neurodegenerative diseases.The study by Fatima et al. 8 provides a mechanism-based approach for the possible role of serum urate in neurodegenerative diseases, in particular, Alzheimer's Disease (AD). As the global aging population grows, the global burden of neurodegenerative diseases becomes a significant unmet public health need. The neuroprotective and antioxidant effects of serum urate are emerging. Therefore, elucidating the possible neuroprotective mechanism could guide a systematic evaluation of the impact of varying serum urate levels on AD. Nonetheless, this study raises more discussion and creates more questions about the double-edged sword effect of urate levels.The published study has some limitations regarding the possible role of other clinical confounders that could impact urate levels. Therefore, more discussion about these limitations could improve future study design. For example, uric acid is primarily eliminated by the kidney, and hence, adjusting for baseline kidney function (i.e., estimated glomerular filtration rate [eGFR]) could have allowed for a better signal-to-noise ratio, especially in a relatively older population. Beside kidney func-This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

The Role of Uric Acid in Human Health: Insights from the Uricase Gene

“…However, the results of these studies have been conflicting or showing no association [ 71 , 72 ]. Partly, these inconclusive findings have been attributed to the study design, not accounting for uric acid level confounders, and the varying degrees of disease progression among study subjects [ 73 ]. While the transport of uric acid into the brain remains elusive, uric acid is produced in the human brain [ 69 ].…”