Skip to content
2000
Volume 23, Issue 12
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

The interconnection between brain function and hyperuricemia remains controversial since the available evidence indicates both the potent neuroprotective role of uric and its negative cardiovascular and metabolic effects, possible prooxidant activity. A mixed (protective and risk) effect of uric acid (UA) on neurological disorders was assumed. Among the neurodegenerative diseases, Alzheimer’s disease remains the most prevalent, causes disability, and lacks highly effective treatments. Therefore, this review aims to delineate the beneficial and detrimental effects of uric acid on Alzheimer’s disease (AD). This can not only facilitate estimating the benefits and risks of urate-lowering or urate-increasing interventions in different conditions but also can enhance understanding of the molecular pathways associated with the protective role of uric acid, leading to the identification of new therapeutic targets for neuroprotection. Firstly, we addressed interconnections between UA and AD in different patients and population subgroups. Secondly, we analysed which differences can arise at the level of uric acid transport to the brain, its influence on blood-brain barrier (BBB), and its presence in brain tissue and cerebrospinal fluid. Such aspects as xanthine oxidase interrelationship with the risk of cognitive impairment was elucidated, as well as the unexpected interconnection between uric acid exchange and the cholinergic system. Finally, an analysis was done of the beneficial and detrimental effects of uric acid on such targets of Alzheimer’s disease pathogenesis as the amyloid-β pathway, proinflammatory markers, peroxynitrite scavenging, and other aspects of prooxidant-antioxidant status.

Loading

Article metrics loading...

/content/journals/cn/10.2174/011570159X349365250128072146
2025-02-18
2025-10-11
Loading full text...

Full text loading...

References

  1. OrowanE. The origin of man.Nature1955175445968368410.1038/175683a0 14370192
    [Google Scholar]
  2. EfroimsonV.P. Genetics of genius.MoscowTaideks Ko Publisher2002376
    [Google Scholar]
  3. NakayamaA. KurajohM. ToyodaY. TakadaT. IchidaK. MatsuoH. Dysuricemia.Biomedicines20231112316910.3390/biomedicines11123169 38137389
    [Google Scholar]
  4. VareldzisR. PerezA. ReisinE. Hyperuricemia: An intriguing connection to metabolic syndrome, diabetes, kidney disease, and hypertension.Curr. Hypertens. Rep.202426623724510.1007/s11906‑024‑01295‑3 38270791
    [Google Scholar]
  5. TovchigaO.V. Shtrygol’S.Y. Uric acid and central nervous system functioning (a literature review).Biol. Bull. Rev.20144321022110.1134/S2079086414030086
    [Google Scholar]
  6. JohnsonR.J. SautinY.Y. OliverW.J. RoncalC. MuW. Gabriela, Sanchez-Lozada, L.; Rodriguez-Iturbe, B.; Nakagawa, T.; Benner, S.A. Lessons from comparative physiology: Could uric acid represent a physiologic alarm signal gone awry in western society?J. Comp. Physiol. B20091791677610.1007/s00360‑008‑0291‑7 18649082
    [Google Scholar]
  7. JohnsonR.J. StenvinkelP. AndrewsP. Sánchez-LozadaL.G. NakagawaT. GaucherE. Andres-HernandoA. Rodriguez-IturbeB. JimenezC.R. GarciaG. KangD.H. TolanD.R. LanaspaM.A. Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts.J. Intern. Med.2020287325226210.1111/joim.12993 31621967
    [Google Scholar]
  8. Sanchez-LozadaL.G. Rodriguez-IturbeB. KelleyE.E. NakagawaT. MaderoM. FeigD.I. BorghiC. PianiF. Cara-FuentesG. BjornstadP. LanaspaM.A. JohnsonR.J. Uric acid and hypertension: An update with recommendations.Am. J. Hypertens.202033758359410.1093/ajh/hpaa044 32179896
    [Google Scholar]
  9. JohnsonR.J. AndrewsP. BennerS.A. OliverW. TheodoreE. Theodore e. woodward award. the evolution of obesity: Insights from the mid-miocene.Trans. Am. Clin. Climatol. Assoc.2010121295305 20697570
    [Google Scholar]
  10. JohnsonR.J. TolanD.R. BredesenD. NagelM. Sánchez-LozadaL.G. FiniM. BurtisS. LanaspaM.A. PerlmutterD. Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?Am. J. Clin. Nutr.2023117345546610.1016/j.ajcnut.2023.01.002 36774227
    [Google Scholar]
  11. MentisA.F.A. DardiotisE. EfthymiouV. ChrousosG.P. Non-genetic risk and protective factors and biomarkers for neurological disorders: A meta-umbrella systematic review of umbrella reviews.BMC Med.2021191610.1186/s12916‑020‑01873‑7 33435977
    [Google Scholar]
  12. MentisA.F.A. DardiotisE. EfthymiouV. ChrousosG.P. Correction to: Non-genetic risk and protective factors and biomarkers for neurological disorders: A meta-umbrella systematic review of umbrella reviews.BMC Med.202119129710.1186/s12916‑021‑02159‑2 34753489
    [Google Scholar]
  13. SinghJ.A. Role of serum urate in neurocognitive function and dementia: New evidence contradicts old thinking.Ann. Rheum. Dis.201877331731810.1136/annrheumdis‑2017‑211975 28939630
    [Google Scholar]
  14. ZhangT. AnY. ShenZ. YangH. JiangJ. ChenL. LuY. XiaY. Serum urate levels and neurodegenerative outcomes: A prospective cohort study and mendelian randomization analysis of the UK biobank.Alzheimers Res. Ther.202416110610.1186/s13195‑024‑01476‑x 38730474
    [Google Scholar]
  15. ŞanlıB.A. WhittakerK.J. MotsiG.K. ShenE. JulianT.H. Cooper-KnockJ. Unbiased metabolome screen links serum urate to risk of Alzheimer’s disease.Neurobiol. Aging202212016717610.1016/j.neurobiolaging.2022.09.004 36206691
    [Google Scholar]
  16. LiuQ. PengM. YangT. SiG. Uric acid levels and risk of cognitive impairment: Dose-response meta-analysis of prospective cohort studies.PLoS One20231811e029383210.1371/journal.pone.0293832 37917590
    [Google Scholar]
  17. WangL. TanZ. WangF.Y. WuW.P. WuJ.C. Gout/hyperuricemia reduces the risk of Alzheimer’s disease: A meta‐analysis based on latest evidence.Brain Behav.20231310e320710.1002/brb3.3207 37667521
    [Google Scholar]
  18. TanaC. TicinesiA. PratiB. NouvenneA. MeschiT. Uric acid and cognitive function in older individuals.Nutrients201810897510.3390/nu10080975 30060474
    [Google Scholar]
  19. LatourteA. SoumaréA. BardinT. Perez-RuizF. DebetteS. RichetteP. Uric acid and incident dementia over 12 years of follow-up: A population-based cohort study.Ann. Rheum. Dis.201877332833510.1136/annrheumdis‑2016‑210767 28754803
    [Google Scholar]
  20. MatsumuraN. AoyamaK. Glutathione-mediated neuroprotective effect of purine derivatives.Int. J. Mol. Sci.202324171306710.3390/ijms241713067 37685879
    [Google Scholar]
  21. KoriM. AydınB. UnalS. ArgaK.Y. KazanD. Metabolic biomarkers and neurodegeneration: A pathway enrichment analysis of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.OMICS2016201164566110.1089/omi.2016.0106 27828769
    [Google Scholar]
  22. GonzalesM.M. GarbarinoV.R. MarquesZ.E. PetersenR.C. KirklandJ.L. TchkoniaT. MusiN. SeshadriS. CraftS. OrrM.E. Senolytic therapy to modulate the progression of Alzheimer’s disease (stomp-ad): A pilot clinical trial.J. Prev. Alzheimers Dis.202191222910.14283/jpad.2021.62 35098970
    [Google Scholar]
  23. OosthoekM. LiliA. AlmeidaA. van LoosbroekO. van der GeestR. de Greef-van der SandtI. van BokhovenP. SikkesS.A.M. TeunissenC.E. VijverbergE.G.B. Asure clinical trial protocol: A randomized, placebo-controlled, proof-of-concept study aiming to evaluate safety and target engagement following administration of tw001 in early Alzheimer’s disease patients.J. Prev. Alzheimers Dis.202310466967410.14283/jpad.2023.107 37874087
    [Google Scholar]
  24. PaganoniS. SchwarzschildM.A. Urate as a marker of risk and progression of neurodegenerative disease.Neurotherapeutics201714114815310.1007/s13311‑016‑0497‑4 27995438
    [Google Scholar]
  25. LiX. HuangL. TangY. HuX. WenC. Gout and risk of dementia, Alzheimer’s disease or vascular dementia: A meta-epidemiology study.Front. Aging Neurosci.202315105180910.3389/fnagi.2023.1051809 37181628
    [Google Scholar]
  26. KimJ.H. YimD.H. ChoiI.A. LeeJ. ParkH. EomS.Y. Impact of clinical association between gout and dementia: A nationwide population‐based cohort study in Korea.Arthritis Care Res.20237551088109410.1002/acr.24959 35604886
    [Google Scholar]
  27. SungW. KwonH.S. ParkY. KimS.H. ParkS. KangD.R. ChoiH. Gout and the prevalence of dementia: A nationwide population-based study.J. Alzheimers Dis.202396134334910.3233/JAD‑230468 37781802
    [Google Scholar]
  28. TopiwalaA. MankiaK. BellS. WebbA. EbmeierK.P. HowardI. WangC. Alfaro-AlmagroF. MillerK. BurgessS. SmithS. NicholsT.E. Association of gout with brain reserve and vulnerability to neurodegenerative disease.Nat. Commun.2023141284410.1038/s41467‑023‑38602‑6 37202397
    [Google Scholar]
  29. SinghJ.A. ClevelandJ.D. Gout and dementia in the elderly: A cohort study of medicare claims.BMC Geriatr.201818128110.1186/s12877‑018‑0975‑0 30428833
    [Google Scholar]
  30. SharmaB. SatijaG. MadanA. GargM. AlamM.M. ShaquiquzzamanM. KhannaS. TiwariP. ParvezS. IqubalA. HaqueS.E. KhanM.A. Role of nlrp3 inflammasome and its inhibitors as emerging therapeutic drug candidate for Alzheimer’s disease: A review of mechanism of activation, regulation, and inhibition.Inflammation2023461568710.1007/s10753‑022‑01730‑0 36006570
    [Google Scholar]
  31. ShaoX. LuW. GaoF. LiD. HuJ. LiY. ZuoZ. JieH. ZhaoY. CenX. Uric acid induces cognitive dysfunction through hippocampal inflammation in rodents and humans.J. Neurosci.20163643109901100510.1523/JNEUROSCI.1480‑16.2016 27798180
    [Google Scholar]
  32. LiuH. ReynoldsG.P. WeiX. The influence of agricultural work and plasma uric acid on hospital admission for Alzheimer’s disease.J. Alzheimers Dis.20239241283128710.3233/JAD‑221226 36872782
    [Google Scholar]
  33. PolidoriM.C. RuggieroC. CroceM.F. RaichiT. MangialascheF. CecchettiR. PeliniL. PaolacciL. ErcolaniS. MecocciP. Association of increased carotid intima–media thickness and lower plasma levels of vitamin C and vitamin E in old age subjects: Implications for Alzheimer’s disease.J. Neural Transm.2015122452353010.1007/s00702‑014‑1357‑1 25585970
    [Google Scholar]
  34. LiuH. ReynoldsG.P. WeiX. Uric acid and high-density lipoprotein cholesterol are differently associated with Alzheimer’s disease and vascular dementia.J. Alzheimers Dis.20207331125113110.3233/JAD‑191111 31884488
    [Google Scholar]
  35. MousaviM. JonssonP. AnttiH. AdolfssonR. NordinA. BergdahlJ. ErikssonK. MoritzT. NilssonL.G. NybergL. Serum metabolomic biomarkers of dementia.Dement. Geriatr. Cogn. Disord. Extra20144225226210.1159/000364816 25177334
    [Google Scholar]
  36. Halperin KuhnsV.L. WoodwardO.M. Sex differences in urate handling.Int. J. Mol. Sci.20202112426910.3390/ijms21124269 32560040
    [Google Scholar]
  37. DesideriG. CastaldoG. LombardiA. MussapM. TestaA. PontremoliR. PunziL. BorghiC. Is it time to revise the normal range of serum uric acid levels?Eur. Rev. Med. Pharmacol. Sci.201418912951306 24867507
    [Google Scholar]
  38. DöringA. GiegerC. MehtaD. GohlkeH. ProkischH. CoassinS. FischerG. HenkeK. KloppN. KronenbergF. PaulweberB. PfeuferA. RosskopfD. VölzkeH. IlligT. MeitingerT. WichmannH.E. MeisingerC. Slc2a9 influences uric acid concentrations with pronounced sex-specific effects.Nat. Genet.200840443043610.1038/ng.107 18327256
    [Google Scholar]
  39. AdamopoulosD. VlassopoulosC. SeitanidesB. ContoyiannisP. VassilopoulosP. The relationship of sex steroids to uric acid levels in plasma and urine.Eur. J. Endocrinol.197785119820810.1530/acta.0.0850198 577077
    [Google Scholar]
  40. HuhK. ShinU.S. ChoiJ.W. LeeS.I. Effect of sex hormones on lipid peroxidation in rat liver.Arch. Pharm. Res.199417210911410.1007/BF02974233 10319141
    [Google Scholar]
  41. WangY. CharcharF.J. Establishment of sex difference in circulating uric acid is associated with higher testosterone and lower sex hormone-binding globulin in adolescent boys.Sci. Rep.20211111732310.1038/s41598‑021‑96959‑4 34462530
    [Google Scholar]
  42. MalobertiA. Dell’OroR. BombelliM. Quarti-TrevanoF. FacchettiR. ManciaG. GrassiG. Long-term increase in serum uric acid and its predictors over a 25 year follow-up: Results of the pamela study.Nutr. Metab. Cardiovasc. Dis.202434122322910.1016/j.numecd.2023.10.009 37996369
    [Google Scholar]
  43. InagakiT. NiimiT. YamamotoT. HashizumeY. OgiharaM. MizunoT. InagakiA. KikuchiM. Sociomedical study of centenarians in nagoya city.Jpn. J. Geriatr.1996332849410.3143/geriatrics.33.84 8656583
    [Google Scholar]
  44. LinX. WangX. LiX. SongL. MengZ. YangQ. ZhangW. GaoY. YangZ. CaiH. BianB. LiY. YuX. DuX. XuS. NieJ. LiuM. SunJ. ZhangQ. GaoY. SongK. WangX. ZhaoL. FanY. Gender- and age-specific differences in the association of hyperuricemia and hypertension: A cross-sectional study.Int. J. Endocrinol.201920191910.1155/2019/7545137 30944567
    [Google Scholar]
  45. KawabeM. SatoA. HoshiT. SakaiS. HirayaD. WatabeH. KakefudaY. IshibashiM. AbeD. TakeyasuN. AonumaK. Gender differences in the association between serum uric acid and prognosis in patients with acute coronary syndrome.J. Cardiol.201667217017610.1016/j.jjcc.2015.05.009 26228000
    [Google Scholar]
  46. KueiderA.M. AnY. TanakaT. Kitner-TrioloM.H. StudenskiS. FerrucciL. ThambisettyM. Sex-dependent associations of serum uric acid with brain function during aging.J. Alzheimers Dis.201760269970610.3233/JAD‑170287 28922153
    [Google Scholar]
  47. BaenaC.P. SuemotoC.K. BarretoS.M. LotufoP.A. BenseñorI. Serum uric acid is associated with better executive function in men but not in women: Baseline assessment of the elsa-brasil study.Exp. Gerontol.201792828610.1016/j.exger.2017.03.010 28300627
    [Google Scholar]
  48. SoysalP. Comment on “serum uric acid is associated with better executive function in men but not in women: Baseline assessment of the elsa-brasil study”.Exp. Gerontol.2017969910.1016/j.exger.2017.06.012 28642074
    [Google Scholar]
  49. MijailovicN.R. VesicK. BorovcaninM.M. The influence of serum uric acid on the brain and cognitive dysfunction.Front. Psychiatry20221382847610.3389/fpsyt.2022.828476 35530021
    [Google Scholar]
  50. McFarlandN.R. BurdettT. DesjardinsC.A. FroschM.P. SchwarzschildM.A. Postmortem brain levels of urate and precursors in Parkinson’s disease and related disorders.Neurodegener. Dis.201312418919810.1159/000346370 23467193
    [Google Scholar]
  51. ZhaoG. GuanJ. Sex-dependent association of serum uric acid levels with amyloid accumulation among amyloid-positive older adults.PLoS One2024192e029673810.1371/journal.pone.0296738 38324515
    [Google Scholar]
  52. ScheepersL.E.J.M. JacobssonL.T.H. KernS. JohanssonL. DehlinM. SkoogI. Urate and risk of Alzheimer’s disease and vascular dementia: A population‐based study.Alzheimers Dement.201915675476310.1016/j.jalz.2019.01.014 31056343
    [Google Scholar]
  53. YeB.S. LeeW.W. HamJ.H. LeeJ.J. LeeP.H. SohnY.H. Does serum uric acid act as a modulator of cerebrospinal fluid Alzheimer’s disease biomarker related cognitive decline?Eur. J. Neurol.201623594895710.1111/ene.12969 26917248
    [Google Scholar]
  54. VannorsdallT.D. KueiderA.M. CarlsonM.C. SchretlenD.J. Higher baseline serum uric acid is associated with poorer cognition but not rates of cognitive decline in women.Exp. Gerontol.20146013613910.1016/j.exger.2014.10.013 25446978
    [Google Scholar]
  55. LeeY. ParkM. JeongS.H. KangS.W. BaikK. JungJ.H. LeeP.H. SohnY.H. YeB.S. Effects of baseline serum uric acid and apolipoprotein e4 on longitudinal cognition and cerebral metabolism.Neurobiol. Aging202110622323110.1016/j.neurobiolaging.2021.05.003 34311431
    [Google Scholar]
  56. LeeY.H. ChungS.J. YooH.S. LeeY. SohnY.H. ChaJ. LeeP.H. Gender-specific effect of urate on white matter integrity in Parkinson’s disease.Parkinsonism Relat. Disord.202075414710.1016/j.parkreldis.2020.05.012 32474403
    [Google Scholar]
  57. FernandesM.A. ProencaM.T. NogueiraA.J. GrazinaM.M. OliveiraL.M. FernandesA.I. SantiagoB. SantanaI. OliveiraC.R. Influence of apolipoprotein e genotype on blood redox status of Alzheimer’s disease patients.Int. J. Mol. Med.19994217918610.3892/ijmm.4.2.179 10402486
    [Google Scholar]
  58. FuW. LuoH. ParthasarathyS. MattsonM.P. Catecholamines potentiate amyloid β-peptide neurotoxicity: Involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis.Neurobiol. Dis.19985422924310.1006/nbdi.1998.0192 9848093
    [Google Scholar]
  59. RovdaIu.I. KazakovaL.M. Purinosis (gouty diathesis) and some diseases of children and adults (urate nephropathy, gout, arterial hypertension, obesity, metabolic syndrome, pancreatic diabetes) [purinosis (neuroarthritic diathesis) and some diseases in children and adults]. Mat’. Dita Kuzb. [Mother and Baby in Kuzbass],20031541822
    [Google Scholar]
  60. TroadecJ.D. MarienM. DariosF. HartmannA. RubergM. ColpaertF. MichelP.P. Noradrenaline provides long‐term protection to dopaminergic neurons by reducing oxidative stress.J. Neurochem.200179120021010.1046/j.1471‑4159.2001.00556.x 11595772
    [Google Scholar]
  61. CascalheiraJ.F. JoãoS.S. PinhançosS.S. CastroR. PalmeiraM. AlmeidaS. FariaM.C. DominguesF.C. Serum homocysteine: Interplay with other circulating and genetic factors in association to Alzheimer’s type dementia.Clin. Biochem.200942978379010.1016/j.clinbiochem.2009.02.006 19232336
    [Google Scholar]
  62. SupakulS. OyamaC. HatakeyamaY. MaedaS. OkanoH. Estradiol enhanced neuronal plasticity and ameliorated astrogliosis in human ipsc-derived neural models.Regen. Ther.20242525026310.1016/j.reth.2023.12.018 38293585
    [Google Scholar]
  63. KimS. KubelkaN.K. LaPorteH.M. KrishnamoorthyV.R. SinghM. Estradiol and 3β-diol protect female cortical astrocytes by regulating connexin 43 gap junctions.Mol. Cell. Endocrinol.202357811204510.1016/j.mce.2023.112045 37595662
    [Google Scholar]
  64. CiarambinoT. CrispinoP. GiordanoM. Hyperuricemia and endothelial function: Is it a simple association or do gender differences play a role in this binomial?Biomedicines20221012306710.3390/biomedicines10123067 36551823
    [Google Scholar]
  65. MaruhashiT. HisatomeI. KiharaY. HigashiY. Hyperuricemia and endothelial function: From molecular background to clinical perspectives.Atherosclerosis201827822623110.1016/j.atherosclerosis.2018.10.007 30326405
    [Google Scholar]
  66. Lucas-HeraldA.K. TouyzR.M. Androgens and androgen receptors as determinants of vascular sex differences across the lifespan.Can. J. Cardiol.202238121854186410.1016/j.cjca.2022.09.018 36156286
    [Google Scholar]
  67. RuizA. PesiniP. EspinosaA. Pérez-GrijalbaV. ValeroS. Sotolongo-GrauO. AlegretM. MonleónI. LafuenteA. BuendíaM. IbarriaM. RuizS. HernándezI. San JoséI. TárragaL. BoadaM. SarasaM. Blood amyloid beta levels in healthy, mild cognitive impairment and Alzheimer’s disease individuals: Replication of diastolic blood pressure correlations and analysis of critical covariates.PLoS One2013811e8133410.1371/journal.pone.0081334 24312290
    [Google Scholar]
  68. ChenG. TongL. YeQ. Association between the serum uric acid/serum creatinine ratio and cognitive function in older adults: Nhanes in the united states.Sci. Rep.20241411631210.1038/s41598‑024‑67580‑y 39009809
    [Google Scholar]
  69. DeLoachT. BeallJ. Diuretics: A possible keystone in upholding cognitive health.Ment. Health Clin.201881334010.9740/mhc.2018.01.033 29955543
    [Google Scholar]
  70. YanJ. ZhengK. ZhangX. JiangY. Fructose consumption is associated with a higher risk of dementia and Alzheimer’s disease: A prospective cohort study.J. Prev. Alzheimers Dis.202310218619210.14283/jpad.2023.7 36946445
    [Google Scholar]
  71. FanningN. MerrimanT.R. DalbethN. StampL.K. An association of smoking with serum urate and gout: A health paradox.Semin. Arthritis Rheum.201847682584210.1016/j.semarthrit.2017.11.004 29398126
    [Google Scholar]
  72. KimT. KimY. KangJ. Association of electronic cigarette exposure with serum uric acid level and hyperuricemia: 2016-2017 korea national health and nutritional examination survey.PLoS One2021163e024786810.1371/journal.pone.0247868 33647052
    [Google Scholar]
  73. RahmaniA. NajandB. SonnegaA. AkhlaghipourG. MendezM.F. AssariS. Intersectional effects of race and educational attainment on memory function of middle-aged and older adults with Alzheimer’s disease.J. Racial Ethn. Health Disparities2024111819110.1007/s40615‑022‑01499‑w 36576695
    [Google Scholar]
  74. ZhouZ. ZhongS. LiangY. ZhangX. ZhangR. KangK. QuH. XuY. ZhaoC. ZhaoM. Serum uric acid and the risk of dementia: A systematic review and meta-analysis.Front. Aging Neurosci.20211362569010.3389/fnagi.2021.625690 33716713
    [Google Scholar]
  75. WangZ. MengL. ShenL. JiH.F. Impact of modifiable risk factors on Alzheimer’s disease: A two-sample mendelian randomization study.Neurobiol. Aging202091167.e11167.e1910.1016/j.neurobiolaging.2020.02.018 32204957
    [Google Scholar]
  76. JiangL. HuX. JinJ. WangW. YuB. ChenG. DongH. ZhouY. Inflammatory risk status shapes the association between uric acid and cognitive function in non-hyperuricemia middle aged and elderly.J. Alzheimers Dis.202497124925710.3233/JAD‑230841 38043014
    [Google Scholar]
  77. WangF. ZhaoM. HanZ. LiD. ZhangS. ZhangY. KongX. SunN. ZhangQ. LeiP. Hyperuricemia as a protective factor for mild cognitive impairment in non-obese elderly.Tohoku J. Exp. Med.20172421374210.1620/tjem.242.37 28529242
    [Google Scholar]
  78. RheeS.J. LeeH. AhnY.M. Association between serum uric acid and depressive symptoms stratified by low-grade inflammation status.Sci. Rep.20211112040510.1038/s41598‑021‑99312‑x 34650110
    [Google Scholar]
  79. QiaoM. ChenC. LiangY. LuoY. WuW. The influence of serum uric acid level on Alzheimer’s disease: A narrative review.BioMed Res. Int.202120211810.1155/2021/5525710 34124244
    [Google Scholar]
  80. FuruhashiM. New insights into purine metabolism in metabolic diseases: Role of xanthine oxidoreductase activity.Am. J. Physiol. Endocrinol. Metab.20203195E827E83410.1152/ajpendo.00378.2020 32893671
    [Google Scholar]
  81. ZhouZ. RyanJ. NelsonM.R. WoodsR.L. OrchardS.G. ZhuC. Gilmartin-ThomasJ.F.M. FravelM.A. OwenA.J. MurrayA.M. EspinozaS.E. ErnstM.E. The association of allopurinol with persistent physical disability and frailty in a large community based older cohort.J. Am. Geriatr. Soc.20237192798280910.1111/jgs.18395 37158186
    [Google Scholar]
  82. Alonso-AndrésP. AlbasanzJ.L. FerrerI. MartínM. Purine‐related metabolites and their converting enzymes are altered in frontal, parietal and temporal cortex at early stages of Alzheimer’s disease pathology.Brain Pathol.201828693394610.1111/bpa.12592 29363833
    [Google Scholar]
  83. HensleyK. MaidtM.L. YuZ. SangH. MarkesberyW.R. FloydR.A. Electrochemical analysis of protein nitrotyrosine and dityrosine in the alzheimer brain indicates region-specific accumulation.J. Neurosci.199818208126813210.1523/JNEUROSCI.18‑20‑08126.1998 9763459
    [Google Scholar]
  84. EsteveC. JonesE.A. KellD.B. BoutinH. McDonnellL.A. Mass spectrometry imaging shows major derangements in neurogranin and in purine metabolism in the triple-knockout 3×tg alzheimer mouse model.Biochim. Biophys. Acta. Proteins Proteomics20171865774775410.1016/j.bbapap.2017.04.002 28411106
    [Google Scholar]
  85. JohnsonR.J. GaucherE.A. SautinY.Y. HendersonG.N. AngerhoferA.J. BennerS.A. The planetary biology of ascorbate and uric acid and their relationship with the epidemic of obesity and cardiovascular disease.Med. Hypotheses2008711223110.1016/j.mehy.2008.01.017 18331782
    [Google Scholar]
  86. BowmanG.L. ShannonJ. FreiB. KayeJ.A. QuinnJ.F. Uric acid as a cns antioxidant.J. Alzheimers Dis.20101941331133610.3233/JAD‑2010‑1330 20061611
    [Google Scholar]
  87. Andres-HernandoA. CicerchiC. KuwabaraM. OrlickyD.J. Sanchez-LozadaL.G. NakagawaT. JohnsonR.J. LanaspaM.A. Umami-induced obesity and metabolic syndrome is mediated by nucleotide degradation and uric acid generation.Nat. Metab.2021391189120110.1038/s42255‑021‑00454‑z 34552272
    [Google Scholar]
  88. ZhangY. QianW. ZhangY. MaY. QianJ. LiJ. WeiX. LongY. WanX. Pediococcus acidilactici reduces tau pathology and ameliorates behavioral deficits in models of neurodegenerative disorders.Cell Commun. Signal.20242218410.1186/s12964‑023‑01419‑3 38291511
    [Google Scholar]
  89. XiaoQ. WangJ. TianQ. TianN. TianQ. HeX. WangY. DongZ. Uric acid mitigates cognitive deficits via TFEB-mediated microglial autophagy in mice models of Alzheimer’s disease.Mol. Neurobiol.20246163678369610.1007/s12035‑023‑03818‑6 38008888
    [Google Scholar]
  90. ShiC. GuoH. LiuX. High uric acid induced hippocampal mitochondrial dysfunction and cognitive impairment involving intramitochondrial NF-κb inhibitor α/nuclear factor-κb pathway.Neuroreport202233310911510.1097/WNR.0000000000001762 35139059
    [Google Scholar]
  91. BeckerB.F. KastenbauerS. KödelU. KieslD. PfisterH.W. Urate oxidation in CSF and blood of patients with inflammatory disorders of the nervous system.Nucleoti. Nucl. Acids2004238-91201120410.1081/NCN‑200027469 15571231
    [Google Scholar]
  92. ReiberH. RuffM. UhrM. Ascorbate concentration in human cerebrospinal fluid (CSF) and serum. intrathecal accumulation and CSF flow rate.Clin. Chim. Acta1993217216317310.1016/0009‑8981(93)90162‑W 8261625
    [Google Scholar]
  93. NiklassonF. HettaJ. DegrellI. Hypoxanthine, xanthine, urate and creatinine concentration gradients in cerebrospinal fluid.Ups. J. Med. Sci.198893322523210.3109/03009738809178548 3238822
    [Google Scholar]
  94. OtaniN. HoshiyamaE. OuchiM. TakekawaH. SuzukiK. Uric acid and neurological disease: A narrative review.Front. Neurol.202314116475610.3389/fneur.2023.1164756 37333005
    [Google Scholar]
  95. WakamatsuK. ChibaY. MurakamiR. MiyaiY. MatsumotoK. KamadaM. NonakaW. UemuraN. YanaseK. UenoM. Metabolites and biomarker compounds of neurodegenerative diseases in cerebrospinal fluid.Metabolites202212434310.3390/metabo12040343 35448530
    [Google Scholar]
  96. UemuraN. MurakamiR. ChibaY. YanaseK. FujiharaR. MashimaM. MatsumotoK. KawauchiM. ShirakamiG. UenoM. Immunoreactivity of urate transporters, glut9 and urat1, is located in epithelial cells of the choroid plexus of human brains.Neurosci. Lett.20176599910310.1016/j.neulet.2017.09.001 28870626
    [Google Scholar]
  97. TomiokaN.H. TamuraY. TakadaT. ShibataS. SuzukiH. UchidaS. HosoyamadaM. Immunohistochemical and in situ hybridization study of urate transporters glut9/uratv1, abcg2, and urat1 in the murine brain.Fluids Barriers CNS20161312210.1186/s12987‑016‑0046‑x 27955673
    [Google Scholar]
  98. TomiokaN.H. NakamuraM. DoshiM. DeguchiY. IchidaK. MorisakiT. HosoyamadaM. Ependymal cells of the mouse brain express urate transporter 1 (urat1).Fluids Barriers CNS20131013110.1186/2045‑8118‑10‑31 24156345
    [Google Scholar]
  99. MorrisM.E. Rodriguez-CruzV. FelmleeM.A. Slc and abc transporters: Expression, localization, and species differences at the blood-brain and the blood-cerebrospinal fluid barriers.AAPS J.20171951317133110.1208/s12248‑017‑0110‑8 28664465
    [Google Scholar]
  100. BurrageE.N. CoblentzT. PrabhuS.S. ChildersR. BrynerR.W. LewisS.E. DeVallanceE. KelleyE.E. ChantlerP.D. Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment.J. Cereb. Blood Flow Metab.202343690592010.1177/0271678X231152551 36655326
    [Google Scholar]
  101. PritsosC.A. Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system.Chem. Biol. Interact.20001291-219520810.1016/S0009‑2797(00)00203‑9 11154741
    [Google Scholar]
  102. TohgiH. AbeT. TakahashiS. KikuchiT. The urate and xanthine concentrations in the cerebrospinal fluid in patients with vascular dementia of the binswanger type, Alzheimer type dementia, and Parkinson’s disease.J. Neural Transm. Park. Dis. Dement. Sect.19936211912610.1007/BF02261005 8117408
    [Google Scholar]
  103. DegrellI. NiklassonF. Purine metabolites in the CSF in presenile and senile dementia of Alzheimer type, and in multi infarct dementia.Arch. Gerontol. Geriatr.19887217317810.1016/0167‑4943(88)90029‑5 3415397
    [Google Scholar]
  104. SpitsinS. KoprowskiH. Role of uric acid in Alzheimer’s disease.J. Alzheimers Dis.20101941337133810.3233/JAD‑2010‑1336 20061607
    [Google Scholar]
  105. RomanY. Pathway for ascertaining the role of uric acid in neurodegenerative diseases.Alzheimers Dement.2022141e1232910.1002/dad2.12329 35769871
    [Google Scholar]
  106. DehlinM. FatimaT. JacobssonL.T.H. KernS. ZettergrenA. BlennowK. ZetterbergH. JohanssonL. SkoogI. Reply to “pathway for ascertaining the role of uric acid in neurodegenerative diseases,” roman youssef.Alzheimers Dement.2022141e1232810.1002/dad2.12328 35769872
    [Google Scholar]
  107. FengJ. ZhengY. GuoM. AresI. MartínezM. Lopez-TorresB. Martínez-LarrañagaM.R. WangX. AnadónA. MartínezM.A. Oxidative stress, the blood–brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants.Acta Pharm. Sin. B202313103988402410.1016/j.apsb.2023.07.010 37799389
    [Google Scholar]
  108. Aliena-ValeroA. Baixauli-MartínJ. Castelló-RuizM. TorregrosaG. HervásD. SalomJ.B. Effect of uric acid in animal models of ischemic stroke: A systematic review and meta-analysis.J. Cereb. Blood Flow Metab.202141470772210.1177/0271678X20967459 33210575
    [Google Scholar]
  109. L’EcuyerS. GilbertK. BrochuB. BeyrouthyJ. LiuC. BouchardC. GagnéM.A. KhazoomF. BernardF. RousseauG. CharbonneyE. Targeting uric acid prevents brain injury and anxiety in a rat model of hemorrhagic shock.Shock202156229830710.1097/SHK.0000000000001708 33394973
    [Google Scholar]
  110. BoltonC. WoodE.G. ScottG.S. FlowerR.J. A comparative evaluation of the response to peroxynitrite by a brain endothelial cell line and control of the effects by drug targeting.Cell. Mol. Neurobiol.200929570771710.1007/s10571‑009‑9391‑5 19330446
    [Google Scholar]
  111. MandalA.K. MountD.B. Interaction between itm2b and glut9 links urate transport to neurodegenerative disorders.Front. Physiol.201910132310.3389/fphys.2019.01323 31695625
    [Google Scholar]
  112. CiprianiS. DesjardinsC.A. BurdettT.C. XuY. XuK. SchwarzschildM.A. Protection of dopaminergic cells by urate requires its accumulation in astrocytes.J. Neurochem.2012123117218110.1111/j.1471‑4159.2012.07820.x 22671773
    [Google Scholar]
  113. WilliamsD.M. HäggS. PedersenN.L. Circulating antioxidants and alzheimer disease prevention: A mendelian randomization study.Am. J. Clin. Nutr.20191091909810.1093/ajcn/nqy225 30596810
    [Google Scholar]
  114. YuanH. YangW. Genetically determined serum uric acid and Alzheimer’s disease risk.J. Alzheimers Dis.20186541259126510.3233/JAD‑180538 30149453
    [Google Scholar]
  115. EfstathiadouA. GillD. McGraneF. QuinnT. DawsonJ. Genetically determined uric acid and the risk of cardiovascular and neurovascular diseases: A mendelian randomization study of outcomes investigated in randomized trials.J. Am. Heart Assoc.2019817e01273810.1161/JAHA.119.012738 31438759
    [Google Scholar]
  116. BoccardiV. CarinoS. MarinelliE. LapennaM. CaironiG. BiancoA.R. CecchettiR. RuggieroC. MecocciP. Uric acid and late-onset Alzheimer’s disease: Results from the regal 2.0 project.Aging Clin. Exp. Res.202133236136610.1007/s40520‑020‑01541‑z 32277437
    [Google Scholar]
  117. SchirinziT. Di LazzaroG. ColonaV.L. ImbrianiP. AlwardatM. SancesarioG.M. MartoranaA. PisaniA. Assessment of serum uric acid as risk factor for tauopathies.J. Neural Transm.201712491105110810.1007/s00702‑017‑1743‑6 28620833
    [Google Scholar]
  118. NatarajanK. UllgrenA. KhoshnoodB. JohanssonC. Laffita-MesaJ.M. PanneeJ. ZetterbergH. BlennowK. GraffC. Plasma metabolomics of presymptomatic psen1 ‐h163y mutation carriers: A pilot study.Ann. Clin. Transl. Neurol.20218357959110.1002/acn3.51296 33476461
    [Google Scholar]
  119. ChourakiV. PreisS.R. YangQ. BeiserA. LiS. LarsonM.G. WeinsteinG. WangT.J. GersztenR.E. VasanR.S. SeshadriS. Association of amine biomarkers with incident dementia and Alzheimer’s disease in the framingham study.Alzheimers Dement.201713121327133610.1016/j.jalz.2017.04.009 28602601
    [Google Scholar]
  120. ParmarM.S. Uric acid and cardiovascular risk.N. Engl. J. Med.20093605539 19186310
    [Google Scholar]
  121. NakayamaA. MatsuoH. OhtaharaA. OginoK. HakodaM. HamadaT. HosoyamadaM. YamaguchiS. HisatomeI. IchidaK. ShinomiyaN. Clinical Practice Guideline for Renal Hypouricemia (1st ed).Human Cell201932838710.1007/s13577‑019‑00239‑3
    [Google Scholar]
  122. FujinagaS. ItoA. NakagawaM. WatanabeT. OhtomoY. ShimizuT. Posterior reversible encephalopathy syndrome with exercise-induced acute kidney injury in renal hypouricemia type 1.Eur. J. Pediatr.2013172111557156010.1007/s00431‑013‑1986‑7 23525542
    [Google Scholar]
  123. MaesakaJ.K. Wolf-KleinG. PiccioneJ.M. MaC.M. Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer’s disease.J. Am. Geriatr. Soc.199341550150610.1111/j.1532‑5415.1993.tb01885.x 8486882
    [Google Scholar]
  124. McCartyM.F. Marinobufagenin and cyclic strain may activate endothelial nadph oxidase, contributing to the adverse impact of salty diets on vascular and cerebral health.Med. Hypotheses201278219119610.1016/j.mehy.2011.09.028 21968275
    [Google Scholar]
  125. JaiswalA. MadaanS. AcharyaN. KumarS. TalwarD. DewaniD. Salivary uric acid: A noninvasive wonder for clinicians?Cureus20211311e1964910.7759/cureus.19649 34956769
    [Google Scholar]
  126. WangC. FeiG. PanX. SangS. WangL. ZhongC. JinL. High thiamine diphosphate level as a protective factor for Alzheimer’s disease.Neurol. Res.20184081810.1080/01616412.2018.1460704 29718773
    [Google Scholar]
  127. ScholefieldM. UnwinR.D. CooperG.J.S. Shared perturbations in the metallome and metabolome of Alzheimer’s, parkinson’s, huntington’s, and dementia with lewy bodies: A systematic review.Ageing Res. Rev.20206310115210.1016/j.arr.2020.101152 32846222
    [Google Scholar]
  128. KimJ.W. ByunM.S. YiD. LeeJ.H. JeonS.Y. KoK. JungG. LeeH.N. LeeJ.Y. SohnC.H. LeeY.S. ShinS.A. KimY.K. LeeD.Y. Serum uric acid, Alzheimer-related brain changes, and cognitive impairment.Front. Aging Neurosci.20201216010.3389/fnagi.2020.00160 32581770
    [Google Scholar]
  129. Molet-BenhamouL. GiudiciK.V. de Souto BarretoP. CantetC. RollandY. VellasB. GuyonnetS. CarriéI. BrigitteL. FaisantC. LalaF. DelrieuJ. VillarsH. CombrouzeE. BadufleC. ZuerasA. AndrieuS. CantetC. MorinC. Abellan van KanG. DupuyC. RollandY. CaillaudC. OussetP.J. LalaF. WillisS. BellevilleS. GilbertB. FontaineF. DartiguesJ.F. MarcetI. DelvaF. FoubertA. CerdaS. CuffiM.N. CostesC. RouaudO. ManckoundiaP. QuipourtV. MarilierS. FranonE. BoriesL. PaderM.L. BassetM.F. LapoujadeB. FaureV. Li Yung TongM. Malick-LoiseauC. Cazaban-CampistronE. DesclauxF. BlatgeC. DantoineT. Laubarie-MouretC. SaulnierI. ClémentJ.P. PicatM.A. Bernard-BourzeixL. WilleboisS. DésormaisI. CardinaudN. BonnefoyM. LivetP. RebaudetP. GédéonC. BurdetC. TerracolF. PesceA. RothS. ChaillouS. LouchartS. SudresK. LebrunN. Barro-BelayguesN. TouchonJ. BennysK. GabelleA. RomanoA. TouatiL. MarelliC. PaysC. RobertP. Le DuffF. GervaisC. GonfrierS. GasnierY. BordesS. BegorreD. CarpuatC. KhalesK. LefebvreJ.F. El IdrissiS.M. SkolilP. SallesJ.P. DufouilC. LehéricyS. ChupinM. ManginJ.F. BouhayiaA. AllardM. RicolfiF. DuboisD. Boncoeur-MartelM.P. CottonF. BonaféA. ChanaletS. HugonF. BonnevilleF. CognardC. CholletF. PayouxP. VoisinT. DelrieuJ. PeifferS. HitzelA. AllardM. ZancaM. MonteilJ. DarcourtJ. MolinierL. DerumeauxH. CostaN. PerretB. VinelC. Caspar-BauguilS. Olivier-AbbalP. AndrieuS. CantetC. ColeyN. Association between urate-lowering therapies and cognitive decline in community-dwelling older adults.Sci. Rep.20221211529910.1038/s41598‑022‑17808‑6 36097005
    [Google Scholar]
  130. MinK.H. KangS.O. OhS.J. HanJ.M. LeeK.E. Association between gout and dementia in the elderly: A nationwide population-based cohort study.Am. J. Geriatr. Psychiatry202129121177118510.1016/j.jagp.2021.01.016 33593591
    [Google Scholar]
  131. LaiS.W. LinC.L. LiaoK.F. Association between allopurinol use and dementia in the elderly.Am. J. Geriatr. Psychiatry202129111174117510.1016/j.jagp.2021.07.014 34400047
    [Google Scholar]
  132. SinghJ.A. ClevelandJ.D. Comparative effectiveness of allopurinol versus febuxostat for preventing incident dementia in older adults: A propensity-matched analysis.Arthritis Res. Ther.201820116710.1186/s13075‑018‑1663‑3 30075731
    [Google Scholar]
  133. SongY. RacetteB.A. Camacho-SotoA. SearlesN.S. Biologic targets of prescription medications and risk of neurodegenerative disease in united states medicare beneficiaries.PLoS One2023185e028501110.1371/journal.pone.0285011 37195983
    [Google Scholar]
  134. YueT.L. McKennaP.J. GuJ.L. ChengH.Y. RuffoloR.E.Jr FeuersteinG.Z. Carvedilol, a new vasodilating adrenoceptor blocker antihypertensive drug, protects endothelial cells from damage initiated by xanthine-xanthine oxidase and neutrophils.Cardiovasc. Res.199428340040610.1093/cvr/28.3.400 7909721
    [Google Scholar]
  135. MartorellM. LucasX. Alarcón-ZapataP. CapóX. Quetglas-LlabrésM.M. TejadaS. SuredaA. Targeting xanthine oxidase by natural products as a therapeutic approach for mental disorders.Curr. Pharm. Des.202127336738210.2174/18734286MTA31NTEh2 32564744
    [Google Scholar]
  136. KessingL.V. RytgaardH.C. GerdsT.A. BerkM. EkstrømC.T. AndersenP.K. New drug candidates for depression – a nationwide population‐based study.Acta Psychiatr. Scand.20191391687710.1111/acps.12957 30182363
    [Google Scholar]
  137. SinghJ.A. ClevelandJ.D. Gout and the risk of incident depression in older adults.Psychiatry Res.201827084284410.1016/j.psychres.2018.10.067 30551333
    [Google Scholar]
  138. LintunenJ. LähteenvuoM. TanskanenA. TiihonenJ. TaipaleH. Allopurinol, dipyridamole and calcium channel blockers in the treatment of bipolar disorder – a nationwide cohort study.J. Affect. Disord.2022313434810.1016/j.jad.2022.06.040 35753501
    [Google Scholar]
  139. LaraD.R. CruzM.R.S. XavierF. SouzaD.O. MoriguchiE.H. Allopurinol for the treatment of aggressive behaviour in patients with dementia.Int. Clin. Psychopharmacol.2003181535510.1097/00004850‑200301000‑00009 12490776
    [Google Scholar]
  140. ZhangQ. LanY. HeX. LuoC. WangQ. LiangF. XuG. PeiZ. Allopurinol protects against ischemic insults in a mouse model of cortical microinfarction.Brain Res.2015162236136710.1016/j.brainres.2015.07.010 26187758
    [Google Scholar]
  141. LlorenteP. KristenH. SastreI. Toledano-ZaragozaA. AldudoJ. RecueroM. BullidoM.J. A free radical-generating system regulates amyloid oligomers: Involvement of cathepsin b.J. Alzheimers Dis.20186641397140810.3233/JAD‑170159 30400084
    [Google Scholar]
  142. BolkeniusF. MonardD. Inactivation of protease nexin-1 by xanthine oxidase-derived free radicals.Neurochem. Int.199526658759210.1016/0197‑0186(94)00177‑V 7670362
    [Google Scholar]
  143. LiX.L. WangP. XieY. Protease nexin-1 protects against Alzheimer’s disease by regulating the sonic hedgehog signaling pathway.Int. J. Neurosci.2021131111087109610.1080/00207454.2020.1773821 32449865
    [Google Scholar]
  144. LockhartB.P. BenicourtC. JunienJ.L. PrivatA. Inhibitors of free radical formation fail to attenuate direct β‐amyloid 25–35 peptide‐mediated neurotoxicity in rat hippocampal cultures.J. Neurosci. Res.199439449450510.1002/jnr.490390416 7533847
    [Google Scholar]
  145. CoelhoF.C. CerchiaroG. AraújoS.E.S. DaherJ.P.L. CardosoS.A. CoelhoG.F. GuimarãesA.G. Is there a connection between the metabolism of copper, sulfur, and molybdenum in Alzheimer’s disease? new insights on disease etiology.Int. J. Mol. Sci.20222314793510.3390/ijms23147935 35887282
    [Google Scholar]
  146. BagnatiM. PeruginiC. CauC. BordoneR. AlbanoE. BellomoG. When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: A study using uric acid.Biochem. J.199934014315210.1042/bj3400143
    [Google Scholar]
  147. MazumderM.K. PhukanB.C. BhattacharjeeA. BorahA. Disturbed purine nucleotide metabolism in chronic kidney disease is a risk factor for cognitive impairment.Med. Hypotheses2018111363910.1016/j.mehy.2017.12.016 29406992
    [Google Scholar]
  148. WamserM.N. LeiteE.F. FerreiraV.V. Delwing-de LimaD. da CruzJ.G.P. WyseA.T.S. Delwing-Dal MagroD. Effect of hypoxanthine, antioxidants and allopurinol on cholinesterase activities in rats.J. Neural Transm.201312091359136710.1007/s00702‑013‑0989‑x 23400363
    [Google Scholar]
  149. BavarescoC.S. ChiaraniF. WajnerM. NettoC.A. de Souza WyseA.T. Intrastriatal hypoxanthine administration affects Na+,] K+‐atpase, acetylcholinesterase and catalase activities in striatum, hippocampus and cerebral cortex of rats.Int. J. Dev. Neurosci.200624741141710.1016/j.ijdevneu.2006.08.007 17034984
    [Google Scholar]
  150. IwakiK. YonetaniY. Hyperuricemic effects of cholinergic agents in rats.Jpn. J. Pharmacol.198232234334910.1016/S0021‑5198(19)52701‑9 7098148
    [Google Scholar]
  151. FabianiC. BiscussiB. MunafóJ.P. MurrayA.P. CorradiJ. AntolliniS.S. New synthetic caffeine analogs as modulators of the cholinergic system.Mol. Pharmacol.2022101315416710.1124/molpharm.121.000415 34969831
    [Google Scholar]
  152. AnsariM.A. ScheffS.W. Oxidative stress in the progression of alzheimer disease in the frontal cortex.J. Neuropathol. Exp. Neurol.201069215516710.1097/NEN.0b013e3181cb5af4 20084018
    [Google Scholar]
  153. GuermonprezL. DucrocqC. Gaudry-TalarmainY.M. Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants.Mol. Pharmacol.2001604838846 11562447
    [Google Scholar]
  154. HaraA. KatsuraM. HigoA. HibinoY. OhkumaS. Enhancement of peroxynitrite-evoked acetylcholine release by hydroxyl radical scavengers from mouse cerebral cortical neurons.Life Sci.1998631082783310.1016/S0024‑3205(98)00339‑7 9734702
    [Google Scholar]
  155. MármolF. SanchezJ. Martínez-PinteñoA. Effects of uric acid on oxidative and nitrosative stress and other related parameters in sh-sy5y human neuroblastoma cells.Prostaglandins Leukot. Essent. Fatty Acids202116510223710.1016/j.plefa.2020.102237 33429354
    [Google Scholar]
  156. YuZ.F. Bruce-KellerA.J. GoodmanY. MattsonM.P. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo.J. Neurosci. Res.199853561362510.1002/(SICI)1097‑4547(19980901)53:5<613::AID‑JNR11>3.0.CO;2‑1 9726432
    [Google Scholar]
  157. SahebnasaghA. EghbaliS. SaghafiF. SuredaA. AvanR. Neurohormetic phytochemicals in the pathogenesis of neurodegenerative diseases.Immun. Ageing20221913610.1186/s12979‑022‑00292‑x 35953850
    [Google Scholar]
  158. Di RosaG. BrunettiG. ScutoM. Trovato SalinaroA. CalabreseE.J. CreaR. Schmitz-LinneweberC. CalabreseV. SaulN. Healthspan enhancement by olive polyphenols in C. elegans wild type and Parkinson’s models.Int. J. Mol. Sci.20202111389310.3390/ijms21113893 32486023
    [Google Scholar]
  159. CalabreseV. CorneliusC. Dinkova-KostovaA.T. CalabreseE.J. MattsonM.P. Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders.Antioxid. Redox Signal.201013111763181110.1089/ars.2009.3074 20446769
    [Google Scholar]
  160. CalabreseV. MancusoC. CalvaniM. RizzarelliE. ButterfieldD.A. Giuffrida StellaA.M. Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity.Nat. Rev. Neurosci.200781076677510.1038/nrn2214 17882254
    [Google Scholar]
  161. CalabreseV. WenzelU. PiccoliT. JacobU.M. NicolosiL. FazzolariG. FaillaG. FritschT. OsakabeN. CalabreseE.J. Investigating hormesis, aging, and neurodegeneration: From bench to clinics.Open Med.20241912024098610.1515/med‑2024‑0986 38911254
    [Google Scholar]
  162. BellasiA. RaggiP. Among markers of risk, uric acid remains a two-faced janus awaiting definitive framing.Atherosclerosis201827221922110.1016/j.atherosclerosis.2018.03.017 29551186
    [Google Scholar]
  163. LiY. ZhaoL. QiW. Uric acid, as a double-edged sword, affects the activity of epidermal growth factor (egf) on human umbilical vein endothelial cells by regulating aging process.Bioengineered20221323877389510.1080/21655979.2022.2027172 35152831
    [Google Scholar]
  164. JinJun Luo X.L. A double-edged sword: Uric acid and neurological disorders.Brain Disord. Ther.20132210910.4172/2168‑975X.1000109
    [Google Scholar]
  165. PopovychI. BombushkarI. ŻukowX. KovalchukH. Uric acid, neuroendocrine-immune complex and metabolism: Relationships.J. Educ. Health Sport202336113515910.12775/JEHS.2023.36.01.013
    [Google Scholar]
  166. GozhenkoA.I. KordaM.M. SmagliyV.S. BadiukN.S. ZukowW. KlishchI.M. KordaI.V. BombushkarI.S. PopovychI.L. Uric acid, metabolism, neuro-endocrine-immune complex.Odesa. Feniks202326610.5281/zenodo.7575158
    [Google Scholar]
  167. CaiZ.X. GuoH.S. WangC. WeiM. ChengC. YangZ.F. ChenY.W. LeW.D. LiS. Double-edged roles of nitric oxide signaling on app processing and amyloid-β production in vitro: Preliminary evidence from sodium nitroprusside.Neurotox. Res.2016291213410.1007/s12640‑015‑9564‑6 26429731
    [Google Scholar]
  168. GuoQ. SebastianL. SopherB.L. MillerM.W. WareC.B. MartinG.M. MattsonM.P. Increased vulnerability of hippocampal neurons from presenilin‐1 mutant knock‐in mice to amyloid β‐peptide tox.J. Neurochem.19997231019102910.1046/j.1471‑4159.1999.0721019.x 10037473
    [Google Scholar]
  169. DesideriG. GentileR. AntonosanteA. BenedettiE. GrassiD. CristianoL. ManocchioA. SelliS. IppolitiR. FerriC. BorghiC. GiordanoA. CiminiA. Uric acid amplifies aβ amyloid effects involved in the cognitive dysfunction/dementia: Evidences from an experimental model in vitro.J. Cell. Physiol.201723251069107810.1002/jcp.25509 27474828
    [Google Scholar]
  170. TranM.H. YamadaK. NakajimaA. MizunoM. HeJ. KameiH. NabeshimaT. Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid β-peptide-induced cholinergic dysfunction.Mol. Psychiatry20038440741210.1038/sj.mp.4001240 12740598
    [Google Scholar]
  171. TianT. LiuX. LiT. NieZ. LiS. TangY. GuC. XuW. JiaH. Detrimental effects of long-term elevated serum uric acid on cognitive function in rats.Sci. Rep.2021111673210.1038/s41598‑021‑86279‑y 33762656
    [Google Scholar]
  172. HuangS. WangJ. FanD.Y. LuoT. LiY. TuY.F. ShenY.Y. ZengG.H. ChenD.W. WangY.R. ChenL.Y. WangY.J. GuoJ. The association of serum uric acid with cognitive impairment and ATN biomarkers.Front. Aging Neurosci.20221494338010.3389/fnagi.2022.943380 35923549
    [Google Scholar]
  173. LiL.L. MaY.H. BiY.L. SunF.R. HuH. HouX.H. XuW. ShenX.N. DongQ. TanL. YangJ.L. YuJ.T. Serum uric acid may aggravate Alzheimer’s disease risk by affecting amyloidosis in cognitively intact older adults: The cable study.J. Alzheimers Dis.202181138940110.3233/JAD‑201192 33814427
    [Google Scholar]
  174. GreenbergS.M. BacskaiB.J. Hernandez-GuillamonM. PruzinJ. SperlingR. van VeluwS.J. Cerebral amyloid angiopathy and alzheimer disease — one peptide, two pathways.Nat. Rev. Neurol.2020161304210.1038/s41582‑019‑0281‑2 31827267
    [Google Scholar]
  175. WangD. WangY. XuD. ZhouG. HeS. Relationship between uric acid and cerebral amyloid angiopathy.Int. J. Neurosci.2023133222223110.1080/00207454.2021.1903001 34913811
    [Google Scholar]
  176. HuQ. LiuA. HuangM. ChengL. KangH. XuF. LiuX. LianL. LiangQ. JiangH. ZhangC. ZhuS. Lower serum uric acid levels in cerebral amyloid angiopathy: A pilot study.Neurol. Sci.20143571035103910.1007/s10072‑014‑1634‑7 24464503
    [Google Scholar]
  177. JonnalaR.R. BuccafuscoJ.J. Inhibition of nerve growth factor signaling by peroxynitrite.J. Neurosci. Res.2001631273410.1002/1097‑4547(20010101)63:1<27::AID‑JNR4>3.0.CO;2‑# 11169611
    [Google Scholar]
  178. MattsonM.P. GoodmanY. LuoH. FuW. FurukawaK. Activation of NF-κB protects hippocampal neurons against oxidative stress-induced apoptosis: Evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration.J. Neurosci. Res.199749668169710.1002/(SICI)1097‑4547(19970915)49:6<681::AID‑JNR3>3.0.CO;2‑3 9335256
    [Google Scholar]
  179. KellerJ.N. KindyM.S. HoltsbergF.W. St ClairD.K. YenH-C. GermeyerA. SteinerS.M. Bruce-KellerA.J. HutchinsJ.B. MattsonM.P. Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: Suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction.J. Neurosci.199818268769710.1523/JNEUROSCI.18‑02‑00687.1998 9425011
    [Google Scholar]
  180. ZhangY.J. XuY.F. LiuY.H. YinJ. LiH.L. WangQ. WangJ.Z. Peroxynitrite induces alzheimer‐like tau modifications and accumulation in rat brain and its underlying mechanisms.FASEB J.20062091431144210.1096/fj.05‑5223com 16816118
    [Google Scholar]
  181. WaughW.H. Inhibition of iron-catalyzed oxidations by attainable uric acid and ascorbic acid levels: Therapeutic implications for Alzheimer’s disease and late cognitive impairment.Gerontology200854423824310.1159/000122618 18367828
    [Google Scholar]
  182. PuZ. XuW. LinY. HeJ. HuangM. Oxidative stress markers and metal ions are correlated with cognitive function in Alzheimer’s disease.Am. J. Alzheimers Dis. Other Demen.201732635335910.1177/1533317517709549 28554217
    [Google Scholar]
  183. GackowskiD. RozalskiR. SiomekA. DziamanT. NicponK. KlimarczykM. AraszkiewiczA. OlinskiR. Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia.J. Neurol. Sci.20082661-2576210.1016/j.jns.2007.08.041 17888453
    [Google Scholar]
/content/journals/cn/10.2174/011570159X349365250128072146
Loading
/content/journals/cn/10.2174/011570159X349365250128072146
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test