Re: 요산.. 산화물질의 60% 제거--＞ 신경보호.. 2022년

[문형철]

REVIEW article

Front. Psychiatry, 22 April 2022

Sec. Molecular Psychiatry

Volume 13 - 2022 | https://doi.org/10.3389/fpsyt.2022.828476

This article is part of the Research TopicNeurobiological Underpinnings of Cognitive Impairment and Pharmacological TreatmentsView all 6 articles

The Influence of Serum Uric Acid on the Brain and Cognitive Dysfunction

Milica M. Borovcanin3*

• 1Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
• 2Department of Neurology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
• 3Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

Uric acid is commonly known for its bad reputation. However, it has been shown that uric acid may be actively involved in neurotoxicity and/or neuroprotection. These effects could be caused by oxidative stress or inflammatory processes localized in the central nervous system, but also by other somatic diseases or systemic conditions. Our interest was to summarize and link the current data on the possible role of uric acid in cognitive functioning. We also focused on the two putative molecular mechanisms related to the pathological effects of uric acid—oxidative stress and inflammatory processes. The hippocampus is a prominent anatomic localization included in expressing uric acid's potential impact on cognitive functioning. In neurodegenerative and mental disorders, uric acid could be involved in a variety of ways in etiopathogenesis and clinical presentation. Hyperuricemia is non-specifically observed more frequently in the general population and after various somatic illnesses. There is increasing evidence to support the hypothesis that hyperuricemia may be beneficial for cognitive functioning because of its antioxidant effects but may also be a potential risk factor for cognitive dysfunction, in part because of increased inflammatory activity. In this context, gender specificities must also be considered.

요산은 

일반적으로 나쁜 평판으로 알려져 있습니다. 

그러나 

요산이 

신경 독성 및/또는 신경 보호에 적극적으로 관여할 수 있다는 사실이 밝혀졌습니다. 

이러한 효과는 

중추신경계에 국한된 산화 스트레스나 염증 과정으로 인해 발생할 수 있지만 

다른 신체 질환이나 전신 질환에 의해서도 발생할 수 있습니다. 

저희의 관심은 

인지 기능에서 요산의 가능한 역할에 대한 최신 데이터를 요약하고 연결하는 것이었습니다. 

또한 

요산 산화 스트레스와 염증 과정의 병리학적인 영향과 관련된 

두 가지 추정 분자 메커니즘에 초점을 맞추었습니다. 

해마는 

요산이 인지 기능에 미치는 잠재적 영향을 표현하는 데 포함되는 

두드러진 해부학적 국소화입니다. 

신경 퇴행성 및 정신 장애에서 요산은 

병인 기전과 임상 증상에 다양한 방식으로 관여할 수 있습니다. 

고요산혈증은 

일반 인구와 다양한 신체 질환 후에 비특이적으로 

더 자주 관찰됩니다. 

고요산혈증이 

항산화 효과로 인해 인지 기능에 도움이 될 수 있다는 가설을 뒷받침하는 증거가 증가하고 있지만, 

부분적으로는 염증 활동 증가로 인해 인지 기능 장애의 잠재적 위험 요인이 될 수도 있습니다. 

요산은 심혈관 질환의 위험 인자이자 세포 손상을 방지하는 주요 천연 항산화제입니다. 요산과 인지 기능 저하 사이의 관계는 혈관 메커니즘과 산화 스트레스가 모두 중요한 역할을 하는 것으로 생각되지만 아직 밝혀지지 않았습니다. 따라서 55세 이상의 참가자 4618명을 대상으로 한 전향적 인구 기반 코호트 연구에서 혈청 요산 수치와 후속 치매 위험 사이의 관계를 평가했습니다. 또한 추적 관찰 기간 동안 치매가 발생하지 않은 1724명의 하위 표본을 대상으로 혈청 요산과 노년기(평균 11.1년 후) 인지 기능 간의 관계를 조사했습니다. 모든 분석은 연령, 성별, 심혈관 위험 요인에 따라 조정되었습니다. 연구 결과, 여러 심혈관 위험 요인을 보정한 후에야 혈청 요산 수치가 높을수록 치매 위험이 감소하는 것으로 나타났습니다(나이, 성별, 심혈관 위험 요인으로 조정한 HR, 요산 표준편차(SD) 증가당 0.89[95% 신뢰구간(CI) 0.80-0.99]). 치매가 없는 참가자의 경우, 기준 시점의 혈청 요산 수치가 높을수록 평가된 모든 인지 영역에서 노년기 인지 기능 개선과 관련이 있었지만[요산 SD 증가당 조정된 Z 점수 차이(95% CI): 전체 인지 기능 0.04(0.00-0.07), 실행 기능 0.02(-0.02-0.06), 기억 기능 0.06(0.02-0.11)] 심혈관 위험 요소를 보정한 후에만 유의한 차이가 나타났습니다. 심혈관 질환의 위험 증가에도 불구하고 요산 수치가 높을수록 치매 위험이 감소하고 노년기 인지 기능이 향상된다는 결론을 내렸습니다.

이러한 맥락에서 성별 특이성도 고려해야 합니다.

Introduction

Uric acid (UA) is the final oxidation product of adenine and guanine metabolism (1). It is formed from these exogenous purines and endogenously from damaged, dying and dead cells (2). In humans, an enzyme called urate oxidase loses its functional activity so that further oxidation of UA is no longer possible. Consequently, humans must cope with much higher levels of UA compared to other mammals (3). UA is generally known for its bad reputation. The fact that about 90% of UA filtered in renal glomeruli is reabsorbed and that humans maintain high levels of UA raised the idea that UA should be considered not only as a metabolic waste but also as a molecule with important physiological activity. The beneficial effects of UA were proposed by Kellog and Fridovich (4) and further explored and developed by Ames et al. (5) three decades ago. In vitro experiments showed that UA is a potent scavenger of singlet oxygen, peroxyl radicals (RO∘22°), and hydroxyl radicals (5). It also protects the cell from oxidative damage by chelating metal ions (6) and acting as a specific inhibitor of radicals generated by the decomposition of peroxynitrite (ONOO−) (7). Because of these effects, UA is considered a very potent free radical scavenger, accounting for more than half of the antioxidant capacity of plasma (8). On the other hand, many epidemiological and experimental data show the oxidative potential of UA. Various cells, after being exposed to UA, generate reactive oxygen species (9). UA, as a pro-oxidant, can decrease nitric oxide (NO) production, induce lipid peroxidation, and interact with peroxynitrite to generate free radicals (9). In recent years, the mechanisms by which UA mediates inflammation have attracted the interest of scientists. UA has been found to contribute importantly to immune responses even in the absence of microbial stimulation (10).

UA (2,6,8 trioxypurine—C5H4N4O3) is a heterocyclic organic compound that is the end product of the oxidation of two purine nucleic acids, adenine and guanine. The enzymatic pathway for the degradation of purines is complex and involves numerous enzymes. Briefly, adenosine monophosphate (AMP) is converted to inosine, while guanine monophosphate (GMP) is converted to guanosine by nucleotidase. The nucleosides, inosine and guanosine, are further converted by purine nucleoside phosphorylase (PNP) to the purine bases hypoxanthine and guanine, respectively. Hypoxanthine is then oxidized to xanthine by xanthine-oxidase (XO) and guanine is deaminated to form xanthine by guanine deaminase. Xanthine is again oxidized by xanthine oxidase to form the final product, UA (11). Being a weak acid with a high dissociation constant, UA circulates in plasma (pH 7.4) predominantly in the form of urate (98%), a monovalent sodium salt (1). UA is mainly formed in the liver, intestine and vascular endothelium from endogenous (nucleoproteins) and exogenous (dietary proteins) precursor proteins (2). Approximately two-thirds of the UA load (65–75%) is excreted by the kidneys, while the gastrointestinal tract eliminates one-third (25–35%) (12). Most of the serum UA is freely filtered in kidney glomeruli, and about 90% of the filtered UA is reabsorbed, while only 10% is excreted in the urine (1).

소개

요산(UA)은

아데닌과 구아닌 대사의 최종 산화 산물입니다(1).

요산은

이러한 외인성 퓨린과 내인성 손상,

죽어가는 세포 및 죽은 세포에서 형성됩니다(2).

사람의 경우

요산 산화효소라는 효소가 기능을 상실하여

더 이상 UA의 산화가 불가능해집니다.

In humans, an enzyme called urate oxidase loses its functional activity so that further oxidation of UA is no longer possible.

따라서

인간은 다른 포유류에 비해

훨씬 더 높은 수준의 요산에 대처해야 합니다(3).

UA는

일반적으로 나쁜 평판으로 알려져 있습니다.

신장 사구체에서 여과된 UA의 약 90%가 재흡수되고

인간이 높은 수준의 UA를 유지한다는 사실은

UA를 대사 폐기물뿐만 아니라

중요한 생리적 활성을 가진 분자로 간주해야 한다는 생각을 불러 일으켰습니다.

UA의 유익한 효과는

켈로그와 프리도비치(4)에 의해 제안되었고,

30년 전에 에임스 등(5)에 의해 더욱 탐구되고 발전되었습니다.

시험관 내 실험에서

UA는

단일 산소, 퍼옥실 라디칼(RO∘22°), 하이드 록실 라디칼(5)을

강력하게 제거하는 것으로 나타났습니다.

또한

금속 이온을 킬레이트화하고(6)

퍼옥시니트라이트(ONOO-)의 분해로 생성되는 라디칼의 특정 억제제 역할을 함으로써

산화적 손상으로부터 세포를 보호합니다(7).

이러한 효과로 인해

UA는

혈장 항산화 능력의 절반 이상을 차지하는

매우 강력한 자유 라디칼 제거제로 간주됩니다(8).

한편, 많은 역학 및 실험 데이터는 UA의 산화 잠재력을 보여줍니다.

다양한 세포가

UA에 노출된 후 활성 산소 종을 생성합니다(9).

항산화제인 UA는

산화질소(NO) 생성을 감소시키고

지질 과산화를 유도하며

퍼옥시니트라이트와 상호 작용하여 자유 라디칼을 생성할 수 있습니다(9).

최근 몇 년 동안

UA가 염증을 매개하는 메커니즘이

과학자들의 관심을 끌고 있습니다.

UA는 미생물 자극이 없는 경우에도 면역 반응에 중요하게 기여하는 것으로 밝혀졌습니다(10).

UA(2,6,8 트리옥시퓨린-C5H4N4O3)는

두 가지 퓨린 핵산인 아데닌과 구아닌의 산화의 최종 산물인

헤테로사이클릭 유기 화합물입니다.

퓨린을 분해하는 효소 경로는 복잡하며

수많은 효소가 관여합니다.

간단히 설명하면,

아데노신 모노포스페이트(AMP)는 이노신으로 전환되고,

구아닌 모노포스페이트(GMP)는 뉴클레오티다아제에 의해 구아노신으로 전환됩니다.

뉴클레오시드인 이노신과 구아노신은

퓨린 뉴클레오시드 인산화효소(PNP)에 의해 각각 퓨린 염기인 하이폭산틴과 구아닌으로 전환됩니다.

그런 다음

하이폭산틴은

크산틴 산화효소(XO)에 의해 크산틴으로 산화되고

구아닌은 구아닌 탈아미나아제에 의해 탈아민화되어 크산틴을 형성합니다.

크산틴은

다시 크산틴 산화효소에 의해 산화되어 최종 생성물인

UA(11)를 형성합니다.

해리 상수가 높은 약산인 UA는

주로 1가 나트륨 염인 요산(98%)의 형태로

혈장(pH 7.4)에서 순환합니다(1).

UA는

주로 내인성(핵 단백질) 및

외인성(식이 단백질) 전구체 단백질로부터

간, 장 및 혈관 내피에서 형성됩니다(2).

SUA 수치가 높을수록 MAFLD 위험이 유의하게 증가했습니다. SUA 수치가 1mg/dL 증가할 때마다 MAFLD 위험이 17%(95% CI 9-24%) 증가했습니다. 또한, 남성은 U자형, 여성은 J자형 연관성을 보이는 것으로 나타났는데, 이는 MAFLD 참가자의 SUA 수치와 모든 원인에 의한 사망률 간에 연관성이 있는 것으로 밝혀졌습니다. 특히 남성의 경우, SUA가 6.7 mg/dL 이상일수록 심뇌혈관 질환(CVD) 사망 위험이 증가하는 것으로 나타났습니다[HR (95% CI): 1.29 (1.05-1.58)]. 여성의 경우, SUA가 5.5mg/dL 이상인 경우에만 CVD 및 암 사망 위험과 유의하게 긍정적인 연관성을 보였습니다[HR (95% CI) 1.62 (1.24-2.13) 및 1.95 (1.41-2.68)]. 결론 SUA 수치의 상승은 MAFLD의 위험 증가와 유의한 관련이 있습니다. 또한 SUA 수치는 MAFLD의 장기 사망률을 예측하는 지표이기도 합니다.

Truth reflex 검사

1. 지방간 간기능 장애로 인해 요산 수치가 상승할 수 있다.  yes

2. 요산수치의 상승으로 인해 지방간, 간기능장애가 발생한다. no

https://www.mdpi.com/2227-9059/11/5/1445#

UA 부하의 약 3분의 2(65-75%)는 신장에서 배설되고,

위장관은 3분의 1(25-35%)을 제거합니다(12).

혈청 UA의 대부분은

신장 사구체에서 자유롭게 여과되고

여과된 UA의 약 90%는 재흡수되며 10%만이 소변으로 배설됩니다(1).

The UA serum level is the result of a balance between dietary purine intake, xanthine oxidase activity, and renal UA excretion (13). When the balance is disturbed, hyperuricemia or hypouricemia occurs. Hyperuricemia has been arbitrarily defined as a value >7 mg/dl in men and >6.5 mg/dl in women, while hypouricemia is defined as a serum urate concentration ≤ 2 mg/dl (14). Numerous epidemiological studies showed elevated UA levels in patients with gout (15), chronic kidney disease (16), cardiovascular diseases (17), metabolic syndrome and obesity (18), confirm‎ing its role as a risk factor and useful marker for prediction of progression and outcome in these diseases.

Hyperuricemia has been studied as a possible driving force in the development of intelligence in primates (19). The presence of hyperuricemia has been shown to confer an evolutionary advantage through greater stimulation of the cerebral cortex (20), which could be attributed to its structural similarity to the known psychostimulant caffeine (19), but has also led to longer life in hominids due to its antioxidant effects (21). These UA metabolic properties may have allowed humans to develop higher brain mass (in terms of volume), better intellectual performance (22), and possibly evolutionary supremacy (20) compared with other mammals. The relationship between hyperuricemia and intellectual activity was then established in different population samples (23, 24). The importance of this relationship has been confirmed at the level of cortical stimulation and/or facilitation of learning processes (22).

Epidemiological studies showed that hyperuricemia is increasing worldwide (25). All these features of elevated UA levels were no longer beneficial but rather became risk factors in modern humans, suggesting that UA plays an important pathogenic role in “diseases of civilization” (26). A recent confluence of biochemical, epidemiological and clinical data has pointed to the far-reaching neuroprotective potential of this endogenous antioxidant but also highlighted its role in inflammatory processes. Although a relatively simple substance, the implications of UA's complex effects on health and disease must be considered.

Understanding the mechanisms by which high UA levels affect neuroplasticity and cognitive functioning could provide a potential therapeutic approach to counteract diseases associated with hyperuricemia. Considering the complexity of the human organism, none of the metabolites, including UA, can be considered one-sidedly. In this article, we attempt to elucidate the role of UA in cognitive functioning based on its involvement in oxidative stress and inflammatory processes.

UA 혈청 수치는

식이 퓨린 섭취,

크산틴 산화효소 활성 및 신장 UA 배설 사이의 균형의 결과입니다(13).

균형이 깨지면 고요산혈증 또는 저요산혈증이 발생합니다.

고요산혈증은 남성의 경우 7 mg/dl 이상, 여성의 경우 6.5mg/dl 이상으로 임의로 정의되었으며, 저요산혈증은 혈청 요산염 농도 ≤ 2mg/dl로 정의됩니다(14). 수많은 역학 연구에서 통풍(15), 만성 신장 질환(16), 심혈관 질환(17), 대사 증후군 및 비만(18) 환자에서 요산 수치가 높아져 이러한 질환의 진행 및 결과 예측에 유용한 마커이자 위험 인자로서의 역할이 확인되었습니다.

고요산혈증은

영장류의 지능 발달의 원동력으로 연구되어 왔습니다(19).

고요산혈증의 존재는

대뇌 피질의 더 큰 자극을 통해

진화적 이점을 제공하는 것으로 나타났는데(20),

이는 알려진 정신 자극제인

카페인과 구조적 유사성 때문일 수 있으며(19),

항산화 효과로 인해 호미닌의 수명 연장으로도 이어졌습니다(21).

이러한

UA 대사 특성으로 인해

인간은 다른 포유류에 비해

뇌 질량(부피), 지적 능력(22), 진화적 우월성(20)을

더 많이 발달시킬 수 있었을 수 있습니다.

고요산혈증과 지적 활동 사이의 관계는 다양한 인구 표본에서 확립되었습니다(23, 24). 이 관계의 중요성은 피질 자극 및/또는 학습 과정의 촉진 수준에서 확인되었습니다(22).

역학 연구에 따르면 고요산혈증이 전 세계적으로 증가하고 있는 것으로 나타났습니다(25). 이러한 UA 수치 상승의 모든 특징은 현대인에게 더 이상 유익한 것이 아니라 오히려 위험 요소가 되었으며, 이는 UA가 “문명의 질병”에서 중요한 병원성 역할을 한다는 것을 시사합니다(26).

최근 생화학, 역학 및 임상 데이터의 융합은

이 내인성 항산화제의 광범위한 신경 보호 잠재력을 지적하는 동시에

염증 과정에서의 역할도 강조했습니다.

https://www.mdpi.com/2072-6643/10/8/975

고요산혈증은 역학 연구에서 독립적인 심혈관 질환 위험 요인으로 인식되어 왔습니다. 그러나 요산은 항산화 특성으로 인해 유익한 기능을 발휘할 수도 있으며, 이는 특히 신경 퇴행성 질환의 맥락에서 관련이 있을 수 있습니다. 이 논문에서는 인지 장애(알츠하이머병, 파킨슨 치매, 혈관성 치매)의 원인과 요산, 치매, 식단 간의 상호 작용에 초점을 맞추어 고령자의 혈청 요산 수치와 인지 기능 사이의 관계에 대한 증거를 비판적으로 재검토합니다. 기존 연구에서는 연구 대상 집단의 특성과 인지 기능 장애 평가 방법이 달라 이질성이 높았음에도 불구하고 혈청 요산이 치매의 원인에 따라 다른 방식으로 인지 기능을 조절할 수 있다는 결론을 내렸습니다. 현재 연구에 따르면 요산은 알츠하이머병과 파킨슨 치매에서 신경 보호 작용을 할 수 있으며, 저요산혈증은 질병 진행을 앞당기는 위험 요소이자 영양실조의 지표가 될 수 있습니다. 반대로 혈청 요산이 높으면 혈관성 치매의 질병 경과에 부정적인 영향을 미칠 수 있습니다. 다양한 치매 유형에서 요산의 생리병리학적 역할과 임상 예후적 중요성을 명확히 밝히기 위해서는 추가 연구가 필요합니다.

비교적 단순한 물질이지만

건강과 질병에 미치는 UA의 복잡한 영향은

반드시 고려해야 합니다.

높은 UA 수치가

신경 가소성과 인지 기능에 영향을 미치는 메커니즘을 이해하면

고요산혈증과 관련된 질병에 대응할 수 있는

잠재적인 치료 접근법을 제공할 수 있습니다.

인체 유기체의 복잡성을 고려할 때

UA를 포함한 대사 산물 중 어느 것도

일방적으로 고려할 수 없습니다.

이 글에서는

산화 스트레스 및 염증 과정과의 관련성을 바탕으로

인지 기능에서 UA의 역할을 규명하고자 합니다.

Methodology

This narrative review was performed by an exhaustive electronic search of the PubMed and Web of Science databases using the terms “uric acid” and “cognition”; “uric acid” and “oxidative stress” “uric acid” and “neuroinflammation;” “uric acid” and “neuroprotection;” “uric acid” and “neurotoxicity”. There was no restriction on the year of publication. We searched for studies published in English, but there were no regional restrictions. We did not pre-specify a preferred study methodology, so there was no restriction on a particular study design. Experimental studies, randomized or non-randomized clinical trials, cohort studies, and case-control studies were considered. We did not limit the assessment of cognitive functioning to a particular test or specify the method of serum UA (sUA) measurement. Abstracts of potentially relevant titles were assessed, and the full text of potentially eligible studies was reviewed. We performed a forward and backward search for relevant papers and repeated this process until no new titles were found. Letters, comments, editorials, practice guidelines, conference proceedings, theses, case studies and unpublished data were excluded.

방법론
이 서술적 검토는 “요산”과 “인지”, “요산”과 “산화 스트레스” “요산”과 “신경염증”, “요산”과 “신경 보호”, “요산”과 “신경 독성” 용어를 사용하여 PubMed 및 Web of Science 데이터베이스의 철저한 전자 검색을 통해 수행되었습니다. 출판 연도에는 제한이 없었습니다. 영어로 발표된 연구를 검색했지만 지역 제한은 없었습니다. 선호하는 연구 방법론을 미리 지정하지 않았기 때문에 특정 연구 디자인에 대한 제한은 없었습니다. 실험 연구, 무작위 또는 비무작위 임상시험, 코호트 연구, 사례 대조군 연구 등이 고려되었습니다. 인지 기능 평가를 특정 검사로 제한하거나 혈청 UA(sUA) 측정 방법을 지정하지 않았습니다. 잠재적으로 관련성이 있는 제목의 초록을 평가하고 잠재적으로 적격인 연구의 전문을 검토했습니다. 관련 논문을 정방향 및 역방향으로 검색하고 새로운 제목이 발견되지 않을 때까지 이 과정을 반복했습니다. 편지, 논평, 사설, 진료 지침, 학회 발표 자료, 논문, 사례 연구 및 미발표 데이터는 제외되었습니다.

Uric Acid and Oxidative Stress

UA acts as a pro-oxidant by increasing free radical production, causing inflammation, and altering the production of NO (27). UA can become a pro-oxidant by forming radicals in reactions with other various oxidants (28), including its relevant interaction with peroxynitrite (27, 29). These radicals predominantly target lipids, low-density lipoprotein (LDL), and membranes rather than other cellular components. At the same time, the hydrophobic environment created by lipids is unfavorable for UA to exert its antioxidative properties. UA cannot scavenge lipophilic radicals and cannot break the radical chain propagation within lipid membranes (30). UA can oxidize LDL in the presence of copper ions (Cu+ and Cu++) and lipid hydroperoxidases (31). UA decreases the bioavailability of NO and inhibits cell migration and proliferation in endothelial cells, mediated in part by C-reactive protein (CRP) expression‎ and oxidative stress (32). It also decreases mitochondrial deoxyribonucleic acid (DNA) contents and intracellular adenosine triphosphate (ATP) concentrations associated with reactive oxygen species (ROS) production (33) (Figure 1A). However, the reaction of UA with peroxynitrite can also generate radicals, consistent with the ability of UA to become pro-oxidant under various circumstances (34).

요산과 산화 스트레스

UA는

활성산소 생성을 증가시키고

염증을 유발하며

NO 생성을 변화시킴으로써 항산화제로 작용합니다(27).

UA는

퍼옥시니트라이트(27, 29)와의 관련 상호작용을 포함하여

다른 다양한 산화제(28)와 반응하여

라디칼을 형성함으로써 항산화제가 될 수 있습니다.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10215565/

요산은 인체에서 퓨린 대사의 최종 산물입니다. 고요산혈증은 혈청 요산(SUA)의 생성 증가 또는 배설 감소로 인해 발생하는 대사성 질환입니다. SUA 항상성의 변화는 여러 질병과 관련이 있으며, 고요산혈증은 통풍의 주요 원인 인자이며 대사 증후군, 심혈관 질환, 당뇨병, 고혈압, 신장 질환과 상관관계가 있는 것으로 알려져 있습니다. 산화 스트레스는 일반적으로 우리 몸의 활성산소와 항산화제 사이의 불균형으로 정의되며 세포 손상과 질병 발생의 주요 원인 중 하나로 간주됩니다. 연구에 따르면 고요산혈증은 활성 산소종(ROS)의 생성과 밀접한 관련이 있는 것으로 나타났습니다. 인체에서 크산틴 산화 환원 효소(XOR)는 저산소산틴을 크산틴에서 요산으로 산화 수산화하는 과정을 촉매하며, 이에 수반되는 ROS 생성을 촉진합니다. 따라서 XOR은 고요산혈증과 통풍 치료를 위한 약물 표적으로 간주됩니다. 이 리뷰에서는 고요산혈증의 발생과 발달에서 산화 스트레스의 역할을 강조하면서 요산 수송 메커니즘과 고요산혈증의 발생에 대해 논의합니다. 또한 XOR 억제제에 대한 최근의 발전과 새로운 발견을 요약합니다.

이러한 라디칼은 다른 세포 구성 요소보다는 지질, 저밀도 지단백질(LDL), 세포막을 주로 표적으로 삼습니다.

동시에 지질에 의해 생성되는 소수성 환경은

UA가 항산화 특성을 발휘하는 데 불리합니다.

UA는

친유성 라디칼을 청소할 수 없으며

지질막 내에서 라디칼 사슬 전파를 끊을 수 없습니다(30).

UA는

구리 이온(Cu+ 및 Cu++)과 지질 과산화효소(31) 존재 하에서

LDL을 산화시킬 수 있습니다.

UA는

NO의 생체 이용률을 감소시키고

내피 세포에서 세포 이동과 증식을 억제하며,

이는 부분적으로 C 반응성 단백질(CRP) 발현과 산화 스트레스에 의해 매개됩니다(32).

또한 미토콘드리아 데옥시리보핵산(DNA) 함량과 활성 산소 종(ROS) 생성과 관련된 세포 내 아데노신 삼인산(ATP) 농도를 감소시킵니다(33)(그림 1A).

그러나

UA와 퍼옥시니트라이트의 반응은 또한 라디칼을 생성할 수 있으며,

이는 다양한 상황에서 UA가 항산화제가 될 수 있는 능력과 일치합니다(34).

FIGURE 1

Figure 1. The role of uric acid in oxidative stress and neuroinflammation. The dual nature of uric acid in terms of oxidative and inflammatory processes in brain tissue. ONOO−, peroxynitrite; NO, nitric oxide; SOD, superoxide dismutase; DNA, deoxyibonucleic acid; oxidative (A,B) and inflammatory processes. (C,D) in brain tissue. ATP, adenosine 5'-triphosphate; NLRP3, nucleotide-binding and oligomerization domain-like receptor protein 3; TLR4, Toll-like receptor 4; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, interleukin; TNF-α, tumor necrosis factor-alpha; CRP, C-reactive protein; STAT 3, signal transducer and activator of transcription 3; BBB, blood-brain barrier.

그림 1. 산화 스트레스와 신경 염증에서 요산의 역할.

뇌 조직의 산화 및 염증 과정 측면에서 요산의 이중적 특성. ONOO-, 퍼옥시니트라이트; NO, 산화 질소; SOD, 슈퍼 옥사이드 디스 뮤 타제; DNA, 데 옥시이보 핵산; 산화 (A,B) 및 염증 과정. (C,D) 뇌 조직에서. ATP, 아데노신 5'-트리인산; NLRP3, 뉴클레오티드 결합 및 올리고머화 도메인 유사 수용체 단백질 3; TLR4, 톨 유사 수용체 4; NF-κB, 활성화된 B 세포의 핵 인자 카파 경쇄 강화제; IL, 인터루킨; TNF-α, 종양 괴사인자 알파; CRP, C 반응 단백질; STAT 3, 신호 전달자 및 전사 3의 활성화제; BBB, 혈액 뇌 장벽.

Oxidative stress has been shown to occur in various cells exposed to UA, such as vascular endothelial cells (32, 33, 35), adipocytes (36), renal tubular cells (37), hepatocytes (38), etc. The high oxygen consumption in neurons leads to the formation of an excessive amount of ROS in the central nervous system (CNS). Compared with other organs, the brain has a lower antioxidant capacity, which makes it particularly vulnerable to oxidative stress (39). The lipid structure of neuronal membranes with unsaturated fatty acids makes neurons extremely sensitive to lipid peroxidation (40). Oxidative damage in the CNS is the result of oxidation and nitration of proteins, lipids, and DNA, leading to necrosis and apoptosis of neuronal cells (41).

UA is a very potent free radical scavenger and is considered one of the most important antioxidants in human plasma (5) (Figure 1B).

It has been suggested that UA may exert neuroprotective effects because of its antioxidant properties. The neuroprotective effect of this purine metabolite was demonstrated in cultured rat hippocampal neurons exposed to excitatory and metabolic toxicity. It also resulted in stabilization of calcium homeostasis and preservation of mitochondrial function (42). Serum UA levels have been shown to have a significant positive correlation with total serum antioxidant capacity in healthy human volunteers after acute administration (41, 43) and also in hypoxia-induced conditions (44). Superoxide dismutase (SOD) is an antioxidant enzyme that scavenges superoxide anion (O−22-) by converting this free radical into oxygen (O2) and hydrogen peroxide (H2O2). Hink et al. demonstrated that UA effectively preserves and enhances extracellular SOD activity in mice at concentrations approaching physiological levels in humans (45). Removal of O−22- prevents its reaction with NO, thus blocking the formation of peroxynitrite (ONOO−), a very potent oxidant implicated in the pathogenesis of several CNS diseases. Peroxynitrite can interact with almost all cellular structures, causing severe cellular damage (46, 47). Squadrito et al. have shown that UA cannot scavenge ONOO− directly but acts as a specific inhibitor of radicals such as CO−33- and NO2, which are formed when ONOO− reacts with CO2 (48). The protective effect of UA against ONOO− was confirmed in the experimental autoimmune encephalomyelitis (EAE) model in mice, which is a model of multiple sclerosis (MS) (49). In mice with developed EAE, exogenously administered UA penetrated the already compromised blood-brain barrier (BBB) and blocked peroxynitrite (ONOO−) mediated tyrosine nitration and apoptotic cell death in inflamed areas of the spinal cord tissue.

UA, as a selective inhibitor of certain peroxynitrite-mediated reactions, blocked the toxic effects of peroxynitrite on primary spinal cord neurons in vitro in a dose-dependent manner and also inhibited both the decline in mitochondrial respiration and the enhanced release of lactate dehydrogenase (LDH) (50). In a mouse model of spinal cord injury (SCI), treatment with UA prevented nitrotyrosine formation, lipid peroxidation, and neutrophil infiltration into spinal cord tissue and significantly improved locomotor dysfunction in mice (50). These results support the possibility that elevating UA levels may provide a therapeutic approach for the treatment of SCI as well as other neurological diseases with a peroxynitrite-mediated pathological substrate.

산화 스트레스는

혈관 내피 세포(32, 33, 35), 지방 세포(36), 신장 관 세포(37), 간세포(38) 등과 같이

UA에 노출된 다양한 세포에서 발생하는 것으로 나타났습니다.

뉴런의 높은 산소 소비량은

중추신경계(CNS)에 과도한 양의 ROS를 형성하게 됩니다.

다른 기관에 비해 뇌는

항산화 능력이 낮기 때문에

산화 스트레스에 특히 취약합니다(39).

불포화 지방산으로 이루어진 신경 세포막의 지질 구조는

뉴런을 지질 과산화에 매우 민감하게 만듭니다(40).

CNS의 산화적 손상은

단백질, 지질 및 DNA의 산화 및 질화의 결과로

신경 세포의 괴사 및 세포 사멸로 이어집니다(41).

UA는

매우 강력한 자유 라디칼 제거제이며

인간 혈장에서 가장 중요한 항산화제 중 하나로 간주됩니다(5)(그림 1B).

UA는

항산화 특성으로 인해

신경 보호 효과를 발휘할 수 있다고 제안되었습니다.

이 퓨린 대사 산물의 신경 보호 효과는

흥분성 및 대사 독성에 노출된 배양된 쥐 해마 신경세포에서 입증되었습니다.

또한

칼슘 항상성을 안정시키고

미토콘드리아 기능을 보존하는 것으로 나타났습니다(42).

혈청 UA 수치는

급성 투여 후

건강한 지원자의 총 혈청 항산화 능력과

유의미한 양의 상관관계가 있는 것으로 나타났으며(41, 43)

저산소증 유발 조건에서도 유의미한 양의 상관관계가 있는 것으로 나타났습니다(44).

슈퍼옥사이드 디스뮤타제(SOD)는

이 활성산소를 산소(O2)와 과산화수소(H2O2)로 전환하여

슈퍼옥사이드 음이온(O-22-)을 청소하는 항산화 효소입니다.

Hink 등은

UA가

사람의 생리적 수준에 근접하는 농도로 생쥐의 세포 외 SOD 활성을

효과적으로 보존하고 향상시킨다는 사실을 입증했습니다(45).

O-22-를 제거하면

NO와의 반응을 방지하여

여러 CNS 질환의 발병에 관여하는

매우 강력한 산화제인 퍼옥시니트라이트(ONOO-)의 형성을 차단합니다.

퍼옥시니트라이트는

거의 모든 세포 구조와 상호 작용하여 심각한 세포 손상을 일으킬 수 있습니다 (46, 47).

Squadrito 등은

UA가 ONOO-를 직접 제거할 수는 없지만

ONOO-가 CO2와 반응할 때 형성되는 CO-33- 및 NO2와 같은

라디칼의 특정 억제제 역할을 한다는 것을 보여주었습니다 (48).

다발성 경화증(MS) 모델인 생쥐의 실험적 자가면역성 뇌척수염(EAE) 모델에서 ONOO-에 대한 UA의 보호 효과가 확인되었습니다(49). EAE가 발병한 마우스에서 외인성 투여된 UA는 이미 손상된 혈액-뇌 장벽(BBB)을 투과하여 척수 조직의 염증 부위에서 퍼옥시니트라이트(ONOO-) 매개 티로신 질화 및 세포 사멸을 차단했습니다.

특정 퍼옥시니트라이트 매개 반응의 선택적 억제제인 UA는 용량 의존적으로 시험관 내에서 일차 척수 뉴런에 대한 퍼옥시니트라이트의 독성 영향을 차단하고 미토콘드리아 호흡의 감소와 젖산 탈수소효소(LDH)의 증가된 방출을 모두 억제했습니다(50). 척수 손상(SCI) 마우스 모델에서 UA로 치료하면 니트로티로신 형성, 지질 과산화 및 척수 조직으로의 호중구 침윤을 방지하고 마우스의 운동 기능 장애를 크게 개선했습니다(50). 이러한 결과는 UA 수치를 높이는 것이 퍼옥시니트라이트 매개 병리학 기질을 가진 다른 신경 질환뿐만 아니라 SCI 치료를 위한 치료적 접근 방식을 제공할 수 있다는 가능성을 뒷받침합니다.

Uric Acid and Inflammation

UA is thought to have a pro-inflammatory effect by triggering interleukin (IL)-1β-mediated inflammation via activation of the nucleotide-binding and oligomerization domain (NOD)-like receptor protein (NLRP) 3 inflammasome, a multimolecular complex whose activation appears to play a central role in many pathological inflammatory conditions (51, 52). It also induces the expression‎ of CRP in human vascular cells (32). Epidemiological studies have shown that UA is positively associated with several pro-inflammatory markers such as CRP, white blood cell count, IL-6 and tumor necrosis factor-alpha (TNF-α), and predicts an increase in their levels over a 3-year follow-up (53, 54). A recent randomized, double-blind, placebo-controlled pilot study revealed the positive correlation between serum UA levels and IL-6, IL-17, and TNF-α, suggesting that xanthine oxidase inhibitors reduce serum UA levels but also the levels of these cytokines in patients with gout (55) (Figure 1A). A positive relationship between serum UA and acute-phase reactants such as CRP, fibrinogen, ferritin, and complement C3 was confirmed in a dose-dependent manner, also suggesting that UA induces the pro-inflammatory effect through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway (56) (Figure 1C).

요산과 염증

요산은

많은 병적 염증 상태에서 활성화가 중심 역할을 하는 것으로 보이는

다분자 복합체인 뉴클레오티드 결합 및 올리고머화 도메인(NOD)-유사 수용체 단백질(NLRP) 3 인플라마좀의 활성화를 통해

인터루킨(IL)-1β 매개 염증을 유발하여

염증 촉진 효과가 있는 것으로 생각됩니다(51, 52).

truth reflex 검사

--> 요산은 병적 염증상태에서 중심역할을 하고, 염증촉진효과가 있다는 위 문장은 옳지 않다. yes

--> 요산수치 증가는 염증의 결과다. 요산수치 증가가 염증의 원인이 아니다. yes

또한

인간 혈관 세포에서

CRP의 발현을 유도합니다(32).

역학 연구에 따르면

UA는 CRP, 백혈구 수, IL-6 및 종양 괴사 인자 알파(TNF-α)와 같은

여러 전 염증성 마커와 긍정적인 관련이 있으며,

3년 추적 관찰 기간 동안 그 수치가 증가할 것으로 예측됩니다(53, 54).

최근의 무작위, 이중맹검, 위약 대조 파일럿 연구에 따르면

혈청 UA 수치와 IL-6, IL-17, TNF-α 간에 양의 상관관계가 있는 것으로 밝혀져

잔틴 산화효소 억제제가 통풍 환자에서 혈청 UA 수치뿐만 아니라

이러한 사이토카인 수치도 감소시키는 것으로 나타났습니다(55)(그림 1A).

--> 위 문장은 300이상이다 yes

혈청 UA와 CRP, 피브리노겐, 페리틴, 보체 C3와 같은 급성기 반응물 사이의 양의 관계가 용량 의존적으로 확인되었으며,

이는 또한 UA가 활성화된 B 세포의 핵 인자 카파 경쇄 강화제(NF-κB) 신호 경로를 통해

염증 효과를 유도함을 시사합니다(56)(그림 1C).

--> 위 문장은 200이상이다 no

Elevated UA levels induced by a high-UA diet (HUAD) triggered the expression‎ of pro-inflammatory cytokines, activated the Toll-like receptor 4 (TLR4)/NF-κB pathway, and increased gliosis in the hippocampus (57) and mediobasal hypothalamus of Wistar rats (58). Furthermore, serum UA was able to cross the BBB and act as a potent inflammatory stimulus (57, 58). Some authors found a linear correlation between serum UA levels and UA levels from cerebrospinal fluid (CSF) and confirmed that BBB impairment was associated with higher CSF levels of UA (59). TLR signaling pathways culminate in the activation of the transcription factor NF-κB, which controls the expression‎ of an array of inflammatory cytokine genes (60). In addition, the activation of the TLR4/NF-κB signaling pathway also occurs in other pathological states which are induced by UA, such as pancreatic β-cell death (61) and renal tubules (62). These results indicate that the pathogenic effect of UA may be manifested by inflammation in the hippocampus, suggesting NF-κB activation as an important signaling pathway. Aliena-Valero et al. demonstrated that exogenous administration of UA increases IL-6 levels and plays a neuroprotective role through the activation of the IL-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway, which in turn leads to modulation of relevant mediators of oxidative stress, neuroinflammation, and apoptotic cell death in the brain (63).

고 UA 식이(HUAD)로 유도된 UA 수치 상승은

전 염증성 사이토카인의 발현을 유발하고,

톨 유사 수용체 4(TLR4)/NF-κB 경로를 활성화하며,

해마(57)와 위스타 쥐의 시상하부(58)에서 신경교세포 증식을 증가시켰습니다.

또한,

혈청 UA는 BBB를 통과하여

강력한 염증 자극으로 작용할 수 있었습니다(57, 58).

--> 위 문장의 진실 수준은 200이상이다 no

--> 혈청 UA는 BBB를 통과하여 항산화 항염증 작용을 한다 YES

일부 저자는 혈청 UA 수치와 뇌척수액(CSF)의 UA 수치 사이에 선형 상관관계가 있음을 발견하고 BBB 손상이 더 높은 CSF UA 수치와 관련이 있음을 확인했습니다(59). TLR 신호 경로는 여러 염증성 사이토카인 유전자의 발현을 조절하는 전사인자 NF-κB의 활성화로 절정에 이릅니다(60). 또한, 췌장 베타세포 사멸(61) 및 신장 세뇨관(62)과 같이 UA에 의해 유도되는 다른 병리학적인 상태에서도 TLR4/NF-κB 신호 경로의 활성화가 발생합니다. 이러한 결과는 UA의 병원성 효과가 해마의 염증에 의해 나타날 수 있음을 나타내며, 중요한 신호 경로로서 NF-κB 활성화를 시사합니다. Aliena-Valero 등은 UA의 외인성 투여가 IL-6 수준을 증가시키고 IL-6/신호 전달체 및 전사인자 3(STAT3) 신호 전달 경로의 활성화를 통해 신경 보호 역할을 하며, 이는 다시 뇌에서 산화 스트레스, 신경 염증 및 세포 사멸의 관련 매개체의 조절로 이어진다는 사실을 입증했습니다(63).

The protective role of UA has also been observed in CNS inflammatory processes. In the EAE model, exogenous treatment with UA prevented disruption of BBB integrity and reduced its permeability to inflammatory cells (49) (Figure 1D). Pre-treatment with UA attenuated meningeal inflammation, BBB, and intracranial hypertension in a dose-dependent manner in the adult rat pneumococcal meningitis model. As UA levels increased to approach levels found in humans, the severity of inflammation decreased as a function of UA concentration (64).

UA의 보호 역할은 CNS 염증 과정에서도 관찰되었습니다. EAE 모델에서 UA를 외인성 처리하면 BBB의 완전성이 파괴되지 않고 염증 세포에 대한 투과성이 감소했습니다(49)(그림 1D). 성인 쥐 폐렴구균성 수막염 모델에서 UA 전처리는 용량 의존적인 방식으로 수막 염증, BBB 및 두개 내 고혈압을 약화시켰습니다. UA 수치가 인간에서 발견되는 수준에 근접할 정도로 증가함에 따라 염증의 심각성은 UA 농도의 함수에 따라 감소했습니다(64).

Uric Acid and Cognitive Functioning

Cognition as a higher brain function consists of major cognitive domains: memory, attention, language, executive functions and visuospatial functions (65). All of these domains can be affected and impaired by certain diseases, processes, or toxins, resulting in cognitive dysfunction (65). Cognitive impairment is a chronic neurodegenerative condition characterized by poor learning and memory (66). Cognitive impairment can be a consequence of the physiological aging process (67, 68), but it can also accompany neurodegenerative (69) and neuropsychiatric disorders (70, 71). It is well-established that oxidative stress and inflammation are important pathogenic mechanisms that lie in the background of these conditions (72–77).

As a potent antioxidant in the human body, but also as a mediator in inflammatory processes, UA is the subject of increasing research focused on its influence on cognitive functioning (summarized in Table 1). Although the impact of UA on cognitive functions is undoubtedly confirmed, the exact mechanisms by which cognitive changes occur are not fully understood.

요산과 인지 기능

고등 뇌 기능으로서의 인지는 기억력, 주의력, 언어, 집행 기능 및 시각 공간 기능(65)과 같은 주요 인지 영역으로 구성됩니다. 이러한 모든 영역은 특정 질병, 과정 또는 독소에 의해 영향을 받고 손상되어 인지 기능 장애를 초래할 수 있습니다(65). 인지 장애는 학습 및 기억력 저하를 특징으로 하는 만성 신경 퇴행성 질환입니다(66). 인지 장애는 생리적 노화 과정의 결과일 수 있지만(67, 68), 신경 퇴행성(69) 및 신경 정신 질환(70, 71)을 동반할 수도 있습니다. 산화 스트레스와 염증이 이러한 질환의 배경에 있는 중요한 병원성 메커니즘이라는 것은 잘 알려져 있습니다(72-77).

인체의 강력한 항산화제이자

염증 과정의 매개체로서 UA는

인지 기능에 미치는 영향에 초점을 맞춘 연구가 증가하고 있습니다( 표 1 에 요약되어 있습니다).

UA가 인지 기능에 미치는 영향은 의심할 여지없이 확인되었지만,

인지 변화가 일어나는 정확한 메커니즘은 완전히 이해되지 않았습니다.

TABLE 1

Table 1. Correlation between serum uric acid levels (sUA) and cognitive functioning (CogF) in various study populations.

The neuroanatomy of cognition should be considered in more detail in this context. The hippocampus is the brain region that plays a critical role in learning and memory (presented in the center of Figure 2). Hippocampal dysfunction can alter cognitive abilities (113). Inflammation of the hippocampus has been associated with various neurological dysfunctions (114, 115). The inflammatory responses also lead to neuronal death and blockade of neurogenesis, which in turn leads to cognitive impairment (116, 117).

FIGURE 2

Figure 2. Potential mechanisms involved in uric acid-related cognitive dysfunction. The summary of the main pathological mechanisms of uric acid, such as oxidative stress and neuroinflammation, along with endothelial dysfunction and excitotoxicity, which may collectively affect neuronal and brain function and further implicate uric acid-related cognitive decline.

In physiological settings, UA levels have been measured in the serum and its values were established to be in the range of 3.5 and 7.2 mg/dL in adult males and postmenopausal women and between 2.6 and 6.0 mg/dL in premenopausal women (118).

Under physiological conditions, the brain relies relatively little on UA for antioxidant defense because UA molecules cannot leak through an intact BBB (119). The relation between UA serum levels and CSF levels represents a crucial aspect in assessing the influence of UA on brain tissue. In healthy subjects, CSF UA levels are about ten times lower than serum levels (120). Examining CSF metabolite in a healthy population sample, Reavis et al. (121) recently found that men have higher CSF UA levels than women [median (25th−75th) 5,353.71 ng/mL (4,041.17–7,102.65) vs. 9,008.48 ng/mL (7,033.92–11,906.72), p < 0.0001]. BBB destruction is thought to play an important role in neuroinflammation and oxidative stress (122). Previous studies have shown that the concentrations of CSF UA in patients with an impaired BBB depend partly on serum UA concentrations and partly on the balance between production and consumption in the CNS (123). Some authors have proposed the CSF-to-plasma UA ratio as a marker of BBB integrity (124). The urate transporter URAT1, expressed on cilia and the apical surface of ventricular ependymal cells lining the wall of the ventricles that separates CSF and brain tissue, may also represent a novel UA transport mechanism involved in the regulation of UA homeostasis in the brain (125). Desideri et al. provided the evidence that UA could exert detrimental effects on brain structure and function by directly influencing the viability of neuronal cells and their ability to establish synaptic connections in the in vitro model of Alzheimer's dementia (AD), depending on the levels of exposure of cells to UA (126). This effect of UA was observed starting from the dose of 40 mM, while lower UA concentration did not significantly influence cell biology, suggesting a dose-dependent effect of this purine metabolite. The reduction of cells viability under UA exposure was observed starting from a dose that could be achieved in CSF in a condition of mild hyperuricemia (i.e., 400 mM) (118). Intraperitoneal injection of UA was found to elevate both plasma and brain urate levels by 55 and 36.8%, respectively, in rats (127). In recent years, there is increasing evidence of positive correlations between CSF UA and sUA levels in patients with neuroinflammatory and neurodegenerative diseases, supporting the hypothesis of a strong influence of UA on the brain and cognition (59, 123, 128). In the presence of hyperuricemia, the diffusion of UA through the BBB could increase the concentrations of UA in CSF to the levels that might exert detrimental effects on cells biology by promoting the onset and/or progression of neuronal damage, further leading to cognitive impairment. It has been shown that each μmol/L increase in plasma UA was associated with about a 5% increase in CSF UA in patients with mild cognitive impairment (59).

Shao et al. showed that systemic hyperuricemia, induced by HUAD in rats over a 12-week period resulted in cognitive dysfunction manifested by decreased spatial learning and memory (57). TLR4 activation can reduce hippocampal pyramidal neuron dendrite length and impair hippocampal-dependent spatial reference memory in an inflammation-dependent manner (129), thus suggesting the potential for TLR4 activation by UA which lead to cognitive impairment. Decreased SOD activity was also detected in the hippocampal tissue of HUAD rats, suggesting pro-oxidant activity of UA. The concentration-dependent correlation between serum levels of UA and hippocampal gliosis has also been confirmed in humans (57). Hypothesizing that the effects of UA on cognition may be related to its concentration and exposure period, Tian et al. explored the effects of long-term elevated serum UA level on cognitive function and hippocampus. This UA elevation induced by HUAD during 48 weeks was significantly associated with the risk of cognitive impairment (130). Elevated UA levels induced oxidative stress and increased the expression‎ of TNF-α and amyloid beta peptide (Aβ) in the rat's hippocampus, suggesting that both oxidative stress and inflammation could mediate the pathogenesis of cognitive impairment induced by UA (130). This study also suggests that the detrimental effects of higher UA levels on cognitive functioning are likely to become apparent only above a certain serum UA concentration. In this review, we have addressed the problems of the possible different impacts of this molecule on cognitive functioning, especially in the context of oxidative and inflammatory changes, and further tried to enlighten its diverse impact of cognition in various neuropsychiatric disorders and regarding somatic functioning in animal models and human studies.

Uric Acid and Cognitive Abilities in an Aging Population

The results of epidemiological studies on the relationship between UA and cognition are conflicting. The study examining the cognitive decline in the population of healthy older women showed that elevated UA levels were associated with poorer working memory and slower manual speed but not with global cognitive functioning, learning/memory, verbal fluency or visuo-constructional functions (84). In the study of elderly adults with mildly elevated UA levels, poorer working and verbal memory were observed compared with those with low-intermediate UA concentrations (80). It has also been shown that even mildly elevated UA levels can lead to both structural and functional brain changes. The results of the Invecchiare in Chianti (InCHIANTI) cross-sectional study suggest a positive association between high circulating levels of UA and the presence of dementia syndrome (82). A positive correlation between circulating UA levels and cognitive decline was demonstrated in a cohort of pharmacologically untreated young elderly subjects (79). In the Rotterdam Scan Study, hyperuricemic patients exhibited white matter atrophy compared to normouremic subjects. This structural change was followed by a deterioration in cognitive abilities, as evidenced by poorer information-processing speed and decreased executive functionality (81). Beydoun et al. showed that in older men, a significant increase in serum UA levels was associated with faster cognitive decline over time in a visual memory/visuo-construction ability test (83). Elevated serum UA levels were associated with changes in spontaneous brain activities and also followed by lower learning/memory and attention/executive functions (78). Lower neuropsychological assessment scores were notably detected in word fluency tests and number connection tests and were observed in males with pre-hyperuricemia and hyperuricemia (78). Because the cognitive changes occurred before hyperuricemia, this finding may be relevant to the clinical management of patients with pre-hyperuricemia and hyperuricemia. These results also suggest that the changes in cognitive functions affected by the different serum UA levels are gender-specific. This study demonstrated that the changes in spontaneous brain activity occurred mainly in the pallidum and putamen, which were correlated with scores of verbal fluency tests and number connection tests. The pallidum and putamen are the structures that make up the basal ganglia, which are involved in motor control and learning and in the selection and activation of cognitive, executive, and emotional programs (131). The gender-related effect has also been observed in some other studies. A study of 1,451 cognitively healthy adults found that elevated baseline sUA was related to decreased attention and visuospatial abilities in males. There were no noticeable findings in females (90). In a large cohort of 1,598 healthy older people, mean age 72 years, with a follow-up of 12 years, Latourte et al. found an increased risk of developing dementia in those with high sUA levels, even after multiple adjustment (91). A strong association was found with vascular or mixed dementia and no significant association with AD. The authors found no significant association between sUA levels and magnetic resonance imaging markers of cerebrovascular disease or hippocampal volume (91). Elevated UA levels could contribute to endothelial dysfunction (132) and subsequent white matter lesions (85) by reducing the availability of NO in the brain, which in turn leads to poorer cognitive performance. In addition, UA could also contribute to endothelial dysfunction through its pro-oxidant properties (133) (see in Figure 2).

In contrary to previous observations, a large prospective population-based cohort study of 4,618 participants aged 55 years and older showed that elevated UA levels were associated with a decreased risk of dementia. Participants without dementia who were followed up later in life and developed hyperuricemia also had better cognitive performance across all cognitive domains assessed in the study but after adjustment for several cardiovascular risk factors (97). Elevated serum UA levels adversely affected subjects with normal cognition, whereas a protective trend was observed in individuals with cognitive impairment. Interestingly, higher sUA levels were associated with a slower decline in cognitive scores and brain metabolism in females with mild cognitive impairment (MCI), and this effect was found in apolipoprotein E4 carriers but not in non-carriers (99). The cohort study of very old people (age 90–108 years) showed that higher sUA levels were associated with a lower risk of cognitive impairment, but only in men (98). This gender-dependent effect was also suggested in a cross-sectional analysis from the Brazilian Longitudinal Study of Adult Health (ELSA-Brazil) cohort (100). Similar results were obtained from studies among Chinese older adults examining the association between blood UA levels and risk for MCI, suggesting a protective role of high blood UA levels. The findings highlight the potential of managing UA in daily life for preserving cognitive abilities in later life (101, 102). High circulating UA levels correlated positively with improved muscle function and cognitive performance in elderly subjects (96). In a prospective study, elevated baseline UA levels were associated with subsequently enhanced cognitive performance, even in the specific cognitive domain (95).

Both vascular pathology and oxidative stress have been associated with increased risk of dementia and cognitive impairment (134, 135). The results of a recent study by Sun et al., demonstrated that serum UA levels were significantly higher in the PSCI group than in the non-PSCI group, suggesting that serum UA levels may serve as a predictive factor for PSCI (93). In the analysis of data from the Impairment of Cognition and Sleep (ICONS) study, both low and high sUA levels were associated with an elevated incidence of PSCI in males but not in females (94). Although UA has potent antioxidant properties, it can accelerate the oxidative stress reaction under certain pathological conditions, such as ischaemia (136, 137).

Several recent systematic reviews have carefully examined the data on sUA and the relationship with dementia/cognition and provided a more comprehensive synthesis of the evidence. The systematic review by Khan and colleagues showed that in 31 studies using mostly case-control data, sUA was lower in dementia patients compared with control subjects without dementia (138). This review concluded that the relationship between sUA and dementia/cognitive impairment was not consistent across dementia groups, with an apparent association for AD and Parkinson's-disease-related dementia (PDD), but not in cases of mixed dementia or Vascular Dementia (VaD). There was no correlation between scores on Mini-Mental State Examination (MMSE) and sUA level, except in patients with PDD. Similar results were provided by the meta-analysis of cohort studies by Pan et al. (139). Another systematic review assessed the association between sUA and AD (140). Based on 11 case-control studies with 2,708 participants, the sUA levels were not significantly different between patients with AD and healthy controls. Thus, on the basis of these systematic reviews, there is no convincing evidence to date that higher sUA levels are associated with a lower risk of dementia, except possibly in PDD.

Uric Acid and Cognitive Abilities in Accompanied Somatic States

Elevated UA levels are an important risk factor for chronic kidney disease (CKD), and numerous studies have shown that these patients are at higher risk for cognitive impairment (86–88). It is also well-established that cerebrovascular lesions are an important risk factor for the development of cognitive decline in CKD patients (141, 142) and that UA plays an important role in these lesions (143, 144). Moreover, direct neuronal injury by uremic toxins can significantly alter cognitive functions in patients at all stages of CKD (87, 145, 146) (summarized in Figure 2). The negative correlation between sUA and MMSE scores was also found in elderly patients receiving maintenance haemodialysis. This correlation was independent of demographic and clinical characteristics (92).

The association between UA and subsequent cognitive performance in patients that carry a high vascular burden showed that low UA levels were associated with poorer cognitive performance, manifested by lower global cognitive scores, memory scores, executive scores, and visuospatial scores (110). A stronger UA effect on cognitive performance was found in older patients (>65 years old), with a significant age interaction for global cognitive, executive, and attention scores. The main finding of this study is that among men with long-lasting cardiovascular diseases and a high vascular burden, lower UA levels were associated with poorer cognitive functions assessed a decade later (110). Higher serum UA levels were independently associated with poorer cognitive performance in chronic heart failure patients (89). Furthermore, these UA effects were manifested in men but not in women.

Uric Acid and Neurodegeneration

The potential contribution of UA to cognitive reserve could be attributed to its potent antioxidant properties. Euser et al. examined the association between serum UA and lower dementia risk and better cognitive function later in life in a large prospective population-based cohort study over an 11-year follow-up period (97). Higher levels of UA were associated with lower dementia risk and better cognitive function in later life. UA has revealed neuroprotective effects after experimental cerebral ischemia (42). These findings support the central role of oxyradicals in excitotoxic and ischemic neuronal injury and suggest a potential therapeutic use of UA in ischemic stroke (refer to Figure 2). Neurological impairment at stroke onset and final infarction size at follow-up were inversely related to the concentration of UA (147). Recent studies on the recovery of cognitive function after stroke by the use of UA may also indicate its possible role in the formation of a cognitive reserve (97).

There is growing evidence that UA may exert neuroprotective properties by suppressing neuroinflammation and inhibiting oxidative stress in neurodegenerative disorders (148, 149). In the experimental model of MS, exogenous treatment with UA prevented disruption of BBB integrity, reduced its permeability to inflammatory cells, decreased oxidative stress, and promoted the survival rate (49). Clinical trials consistently suggest that higher serum UA levels are related to a slower progression of Parkinson's disease (PD) (103, 104). PD patients with cognitive dysfunction also have lower serum levels of UA compared to those without cognitive dysfunction (111). The controlled longitudinal study that examined the evolution of cognitive changes and the prognostic value of the UA levels on cognition in the PD-patient cohort demonstrated that the level of both plasma and sUA remained stable over the 3-year period with subtle cognitive changes (150). Given that UA may have a neuroprotective effect in PD, maintaining or even increasing the sUA levels would be beneficial for PD-patients. This study also suggests that it is important to keep body weight and diet stable to avoid fluctuations in UA levels. Recent epidemiological studies showed decreased levels of UA in amyotrophic lateral sclerosis (ALS) patients compared to matched controls and subsequently linked higher UA baseline levels with slower progression and prolonged survival (105–107). In Huntington's disease, functional decline was negatively correlated with UA levels (108). The inverse association between serum UA and AD risk was confirmed in the meta-analysis by Du et al. (109). Patients with depression seem to have significantly lower serum UA levels compared to patients with delirium, dementia, amnesia, and other cognitive disorders (112). The decrease in serum UA levels was related to the antimanic, anticonvulsant, and antiagressive effects of lithium and allopurinol (151). UA levels were also decreased in subjects with first-episode psychosis (152), and further reduced plasma UA levels suggest a defect in the antioxidant defense system in schizophrenia (153). Numerous studies have shown that serum UA levels were lower or tended to decrease in patients with neurodegenerative and mental disorders. Increased serum UA levels could reduce the risk of onset and slow the progression of cognitive decline, thus confirm‎ing the hypothesis of a protective role of UA in these disorders (Figure 1B). Opposite to these results, recent research by Borovcanin et al. pointed to the correlation of sUA levels with negative symptoms in patients with schizophrenia after acute treatment, especially important when considering that negative symptoms and cognitive deficits in schizophrenia share many features (154).

Conclusion

Based on the results of experimental and clinical studies, UA seems to play a dual role as a pro- and antioxidant. The balance between the two effects reflects a very complex interplay of factors that include the concentration of UA, the nature and concentration of free radicals, the presence and concentration of other antioxidant molecules, and the various cascades involved (155). However, recent studies suggest that the antioxidant properties of UA are not solely responsible for its beneficial effects in the CNS. UA has been recognized as an important metabolite in protecting spinal cord neurons from glutamate-induced toxicity (156). UA is also thought to have beneficial effects within the normal range, whereas detrimental effects are more likely to occur in hyperuricemia.

Recently, however, there has been a growing body of evidence from clinical and basic research supporting the hypothesis that hyperuricemia, in part through increased inflammatory activity, may be a potential risk factor for cognitive dysfunction. Taking these lines of evidence together, UA appears to exert a protective effect on brain tissue and neurons during the initial stage of elevated UA levels, primarily through its potent antioxidant activity, but long-term elevation appears to trigger an inflammatory response that leads to brain tissue damage. Thus, UA metabolism may be a so-called double-edged sword in terms of the inflammatory and/or oxidative responses it induces in brain tissue, although, its harmful effects appear to outweigh the benefits of UA in most cases.

Although numerous factors contributing to cognitive impairment have been identified to date, UA appears to be an important participant in the onset and/or progression of cognitive decline in various disorders. There is still conflicting evidence about UA's pathophysiological role and its clinical significance in influencing cognitive dysfunction. This may be partly explained by UA's dual nature and different properties, but also by a variety of distinct pathologies that can lead to many constellations of cognitive domain's dysfunctions.

Future Perspectives

The UA impact on cognitive abilities may have a long evolution course, suggesting that the effects of UA on cognition should be explored in the terms of long, chronic exposure. The more informative study design would be a prospective long-term follow-up cohort study with a relatively large sample of older adults and measurement of sUA fluctuations concurrently with cognitive testing. Cognitive functions should be assessed with a wider range of domain-specific neurological tests. This would allow us to understand global patterns of cognitive fluctuation over time. In this context, it would also be important to investigate accompanying neuroanatomical and neurophysiological changes. Identification of modifiable risk factors is also important, as this will provide greater insight into pathophysiology, risk stratification and potential interventions. Collection of data on dietary habits, medication and comorbidity is necessary to fully exclude the influence of confounding factors. Further research on these complex topics is needed to help design and implement interventions to preserve cognitive capacities in health and various diseases.

Author Contributions

MB presented the idea and initial structuration of this review article. NM and KV drew a figure and a table. All authors have searched the literature and given some new insights into specific fields of their competencies, read, discussed, and accepted responsibility for the entire content of this submitted manuscript and approved its submission.

Funding

This work was supported by the Ministry of Science and Technological Development of the Republic of Serbia, No. 175069 and the Faculty of Medical Sciences, University of Kragujevac, No. JP 03/16.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be eval‎uated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We thank Bojana Mircetic for language editing.

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