Role of uric acid in neurodegenerative diseases, focusing on Alzheimer and Parkinson disease: A new perspective

Abstract

Neurodegenerative diseases (NDs) such as Alzheimer disease (AD) and Parkinson disease (PD) are group of diseases affecting the central nervous system (CNS) characterized by progressive neurodegenerations and cognitive impairment. Findings from different studies highlighted the beneficial and detrimental effects of serum uric acid on the development and progression of NDs. Therefore, this mini‐review aims to discuss the beneficial and detrimental effects of uric on NDs. The neuroprotective effect of uric acid is mainly related to the antioxidant effect of uric acid which alleviates oxidative stress‐induced neurodegeneration in AD and PD. However, long‐term effect of hyperuricemia prompts for the development and progression of cognitive impairment. Hyperuricemia is associated with cognitive impairment and dementia, and gout increases dementia risk. In addition, hyperuricemia can cause cerebral vascular injury which is a risk factor for vascular dementia and cognitive impairment. Taken together, the relationship between uric acid and NDs risk remains conflicting. Hence, preclinical and clinical studies are indicated in this regard.

INTRODUCTION

Neurodegenerative diseases (NDs) are group of diseases affecting the central nervous system (CNS) including Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington disease (HD) characterized by progressive neurodegenerations in specific brain regions.^1,2 Environmental and genetic risk factors are interrelated in the development and progression of NDs through induction of mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, neuroinflammation, and neuronal apoptosis.³ The pathological hallmark of NDs is often linked to the aggregation of specific proteins due to overproduction or defective clearance of these misfolded proteins.⁴

In AD which is the most common ND, progressive intracellular accumulation of tau protein-forming neurofibrillary tangles (NFTs) and extracellular accumulation of non-soluble amyloid beta (Aβ) are evident.⁵ In PD which is the second ND, there is progressive accumulation of alpha synuclein (α-Syn) in the dopaminergic neurons of substantia nigra pars compacta (SNpc).⁶ These misfolded proteins induce neurotoxic effects directly or indirectly through activation the formation of reactive oxygen species (ROS), mitochondrial dysfunction, ER stress, excitotoxicity, and impairment of synaptic functions.⁷

Aging represents the major risk factor for the development of NDs, as most of NDs are more frequent after the age of 65 years.⁸ Therefore, NDs are considered as age-related disorders due to initiation of neuronal loss.⁹ However, neuronal loss in aging process is limited to certain brain regions, though progressive neuronal loss is augmented in NDs⁹ (Figure 1).

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In 2050, the global population over age of 60 years is expected to reach 22% compared to 2015 due to lifestyle modification and early management of different diseases.¹⁰ Therefore, the prevalence and incidence of NDs because of increasing elderly population may be augmented.

On the other hand, findings from different studies highlighted the neuroprotective role uric acid against the development and progression of NDs.¹¹ Though, recent studies indicated that high level of uric acid may act as prooxidant causing oxidative and cognitive impairment.¹² Thus, this mini-review is intended to discuss the beneficial and detrimental effects of uric on NDs mainly in AD and PD.

Uric acid overview

Uric acid is the natural end product of endogenous guanine and adenine metabolism from injured cells. In addition, exogenous purine from diet is another source for the formation of uric acid.¹² Adenosine monophosphate (AMP) and guanine monophosphate (GMP) are converted to inosine and guanosine, respectively, to form hypoxanthine which via xanthine oxidase is converted to xanthine and then to uric acid¹³ (Figure 2).

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Uric acid is primarily synthesized by liver, intestines, and vascular endothelium, and 75% of uric acid is excreted by kidney,¹³ and 25% is excreted by intestines.¹⁴ However, 90% of secreted uric acid is reabsorbed from proximal tubules, and 10% is excreted by urine.¹⁴ Uric acid is regarded as a weak acid, dissociated in the plasma to form urate 98% and monovalent sodium salt 2%.¹⁵ Uric acid in the blood reflects the balance between the production and the excretion of uric acid. Increasing of serum uric acid >6.5 mg/dL in women, and >7.0 mg/dL in men is define as hyperuricemia.¹³ Though, reduction of serum uric acid below the reference range is called hypouricemia.¹⁶ Hyperuricemia is regarded as a risk factor for gout, chronic kidney diseases, cardiovascular complications, and metabolic syndrome¹⁷ (Figure 3).

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Uric acid is regarded an active molecule, and not as waste product since kidney reabsorbed 90% of it to maintain its blood level. The potential protective effect of uric acid is related to its antioxidant effects by scavenging ROS and peroxynitrite.¹⁸ Therefore, uric acid is regarded as a potent antioxidant agent that represents 50%–70% of total body antioxidant.¹⁹ However, uric acid may act as prooxidant to form ROS and free radicals by inhibiting the production of nitric oxide. In addition, uric acid through interaction with peroxynitrite can generate free radicals which cause lipid peroxidation.²⁰

BENEFICIAL EFFECTS OF URIC ACID ON NDs

Most of clinical studies illustrated that uric acid acts as a potent endogenous antioxidant reduces the development and progression of NDs.^21,22 A cross-sectional study involved 840 patients with different types of NDs compared to 839 healthy controls showed that serum uric acid was reduced in patients with NDs compared to healthy controls.²¹ A cohort study involved 111 patients with tauopathies and 130 healthy controls confirmed that low serum uric acid is associated with tauopathies compared to healthy controls.²³ A case–control study illustrated that serum uric acid is lower in PD patients (n = 1061) compared to healthy controls (n = 754).²² In addition, high serum uric acid is negatively associated with non-motor symptoms in PD patients.²⁴ Zhou et al.²⁵ illustrated that low serum uric acid is associated with poor sleep in PD patients. As well, a systematic review and meta-analysis unveiled that serum uric acid is low in PD.²⁶ Likewise, a systematic review and meta-analysis indicated that low serum uric acid is correlated with increasing risk of dementia.²⁷ A systematic review and meta-analysis showed that serum uric acid is low in patients with ALS.²⁸ Interestingly, a longitudinal study on 313 sporadic ALS and 16 familial ALS patients showed that lower baseline serum uric acid is linked with shorter survival suggesting an inverse relationship between serum uric acid and mortality risk in ALS.²⁹ Chen et al., revealed that serum uric acid is low in ALS patients compared to healthy controls.³⁰ A systematic review and meta-analysis showed that serum uric acid is low in patients with ALS.²⁸ These findings suggest the neuroprotective effect of hyperuricemia against NDs mainly in PD.

Furthermore, hyperuricemia is often associated with the development of gout which is an inflammatory disorder of joints and soft tissues due to deposition of urate crystals.³¹ A nation-wide population-based cohort study illustrated no significant association between gout and PD risk.³¹ Similarly, a retrospective study in Taiwan did not find any association between gout and PD risk.³² Moreover, a Mendelian randomized study found no significant association between gout and AD.³³ A recent a systematic review and meta-analysis showed that both of hyperuricemia and gout have a protective effect against the development and progression of AD.³⁴ In addition, hyperuricemia and gout have a protective effect against ALS.³⁵ A nationwide population study observed that gout reduces the incidence and severity of ALS and other motor neuron diseases suggested the neuroprotective effect of uric acid against the development and progression of ALS.³⁵ Thus, hyperuricemia and gout seem to have neuroprotective effects against the development and progression of NDs.

The underlying neuroprotective effect of uric acid against PD neuropathology is through inhibiting the accumulation of α-Syn by inducing neuronal autophagy via mTOR-dependent pathway.²⁴ Similarly, uric acid improves memory and cognitive function in mice model by inducing neuronal autophagy which facilitates Aβ clearance.³⁶ The neuroprotective effect of uric acid is related to its antioxidant effect which mitigates oxidative stress-induced neurodegeneration. The antioxidant effect of uric acid is depending on the presence of astroglia by increasing the expression of glutamate transporters which reduce glutamate-induced neurotoxicity.³⁷ In addition, uric acid is produced locally in ischemic and inflammatory neurological disorders as a compensatory mechanism against oxidative stress-induced overconsumption of uric acid.³⁸ It has been shown that administration of exogenous uric acid exerts a neuroprotective effect in experimental neurological disorders such as brain ischemia, experimental autoimmune encephalomyelitis (EAE), spinal cord injury, and meningitis.³⁹ Uric acid exerts an additive effect with thrombolytic alteplase in experimental ischemic stroke.³⁹ A clinical trial highlighted that uric acid in combination with alteplase improves the clinical outcomes in patients with ischemic stroke by inhibiting the generation of malondialdehyde (MDA) and activation of matrix metalloproteinase 9 (MMP9).³⁹ Furthermore, administration of uric acid promotes survival and reduces disease severity in EAE mouse model and experimental PD.⁴⁰ Also, treatment of multiple sclerosis (MS) patients with uric acid precursor inosine attenuates the disease severity.⁴¹ Therefore, uric acid prevents derangement of BBB and lipid peroxidation in acute ischemic stroke. Indeed, ischemic stroke and MS are associated with the development neurodegeneration due to oxidative stress and neuroinflammation.^42,43

Of note, oxidative stress is the most proposed theory in the development of NDs.⁴⁴ However, the use of antioxidant agents such as vitamin E and CoQ10 in NDs result in disappointment findings.⁴⁵

Furthermore, uric acid has an iron-chelating property preventing iron accumulation within neurons.⁴⁶ Accumulation of iron within the dopaminergic neurons in the SNpc is a pathological hallmark of PD, causing misfolding of α-Syn. Therefore, low serum uric acid promotes iron accumulation in the SNpc leading to progression of PD neuropathology.⁴⁶

Of interest, uric acid has stimulatory effect on the cerebral cortex due to structural similarity with psychomotor stimulant caffeine. It improves learning and cognitive functions, enhances motivations and behavioral responses.⁴⁷ However, under normal physiological status, the brain depends little on the antioxidant effect of uric acid as it does not cross BBB.⁴⁸ In healthy subjects, uric acid concentration in the cerebrospinal fluid (CSF) is 10-fold lower than serum uric acid.⁴⁹ A cohort study on 31 AD patients followed for 1 year, showed that plasma and CSF uric acid levels were increased and correlated with cognitive impairments compared to the baseline levels.⁴⁹ Therefore, BBB derangement due to oxidative stress and neuroinflammation in NDs might be the underlying cause for elevation of CSF uric acid level. Thus, CSF/plasma uric acid ratio represents a tool for BBB integrity.⁵⁰ However, experimental study confirmed that uric acid transporter 1 is highly expressed in the ependymal cells of brain ventricles contribute in the transport of uric acid into the CSF.⁵¹ Polymorphism of uric acid transporter 1 which increases CSF transport of uric have been shown to improve cognitive function in elderly subjects.⁵² Of interest, in PD patients who had more genetic variants, there is significant hyperuricemia suggesting a link between PD genetic variant and uric acid transporters.²²

These observations and fundamental studies indicated that hyperuricemia has a protective against the development and progression of NDs through antioxidant property, chelating Fenton reaction transitional metals, and electron donor which increase the activity of antioxidant enzymes such as superoxide dismutase (SOD) (Table 1).

TABLE 1 The protective role of hyperuricemia against the development of NDs.

Ref.	Type of the study	Findings
21	A cross-sectional study	Serum uric acid is reduced in patients with NDs compared to healthy controls
23	A cohort study	Low serum uric acid is associated with tauopathies compared to healthy controls
22	A case–control study	Serum uric acid is low in PD patients compared to healthy controls
24	A preclinical study	High serum uric acid is negatively associated with non-motor symptoms in PD
25	A case–control study	Low serum uric acid is associated with poor sleep in PD patients
29	A longitudinal study	An inverse relationship between serum uric acid and mortality risk in ALS
30	A case–control study	Serum uric acid is low in ALS patients compared to healthy controls
35	A cohort study	Hyperuricemia and gout have protective effects against ALS
36	A preclinical study	Uric acid improves memory and cognitive function in mice
39	A preclinical study	Administration of exogenous uric acid exerts a neuroprotective effect in EAE
41	A preclinical study	Uric acid promotes survival and reduces disease severity in EAE and experimental PD
46	A preclinical study	Low serum uric acid promotes iron accumulation in the SNpc leading to the progression of PD neuropathology

DETRIMENTAL EFFECTS OF URIC ACID ON NDs

It has been shown that long-term effect of hyperuricemia predisposes for the development and progression of cognitive impairment by inducing oxidative stress, release of pro-inflammatory tumor necrosis factor alpha (TNF-α) and accumulation of Aβ.⁵³ Preclinical study demonstrated that established hyperuricemia in rats within 6 weeks induces cognitive impairment at 48 weeks.⁵³ In Rotterdam study, high serum uric acid is correlated with cognitive impairment and white matter atrophy.⁵⁴ Furthermore, a prospective study illustrated that high basal level of serum uric acid is connected with cognitive decline and memory impairment.⁵⁵ The relationship between serum uric acid and cognitive function is U shape in T2D patients.⁵⁶ Notably, gout patients have small brain volume, and vulnerable for time-dependent neurodegenerative diseases in the first 3 years from time of gout diagnosis.⁵⁷ Cerebellar atrophy-induced tremor is highly observed in gout patients.⁵⁸ Furthermore, hyperuricemia and gout augment AD risk⁵⁹ and regarded as modifiable risk factor for other NDs.⁶⁰ A longitudinal study involved Korean gout patients followed for 12 years illustrated that gout increases risk of AD and PD mainly below age of 60 years.⁶¹ Singh et al.⁶² reported that gout augments PD risk by 14%.⁶² In addition, observational studies revealed that hyperuricemia is associated with cognitive impairment and dementia.⁶³ Of note, gout increases dementia risk by 15% in older subjects.⁶⁴

Notably, high uric acid concentration can cross deranged BBB and deposited in specific brain regions mainly in the hippocampus causal hippocampal inflammation which predispose for neurodegeneration.⁶⁵ High uric acid concentration in brain activates microglia and astroglia with development of reactive astrogliosis leading to neuroinflammation by triggering the release of pro-inflammatory cytokine and progression of cognitive dysfunction.⁶⁵ Uric acid via activation of toll-like receptor 4 (TLR4) triggers the activation of myeloid differentiation primary response 88 (MYD88) and increases the expression of nuclear factor kappa B (NF-κB) and subsequent expression of pro-IL-1β. Hypoxia inducible factor 1 alpha (HIF-1α) which promotes the conversion of pro-IL-1β to the IL-1β and via IL-1β receptor reactivates the expression of the NF-κB. Finally, IL-1β triggers hippocampal inflammation and the development of cognitive impairment.⁶⁵ Prolonged hippocampal inflammation induces cognitive impairment by inhibiting neurogenesis and augmenting neuronal apoptosis.^65,66 Prolonged hippocampal inflammation induces cognitive impairment by inhibiting neurogenesis and augmenting neuronal apoptosis (Figure 4).

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Indeed, hyperuricemia has pro-inflammatory effects by inducing the expression of nod-like receptor pyrin 3 (NLRP3) inflammasome, TNF-α, IL-6, and IL-17. As well, hyperuricemia promotes complement C3, ferritin, fibrinogen, and CRP.⁶⁷ Of note, acute microglia activation and the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-17 is a possible protective mechanism against neuronal injury. However, chronic microglial activation result in progressive neuronal injury and contribute in the progression of NDs.⁶⁸ Particularly, NLRP3 inflammasome is activated in response to the neuronal injury in NDs. Exaggerated immune response and NLRP3 inflammasome activation induce aggressive neurodegeneration in AD, PD, ALS, and MS.⁶⁹ Prolonged inflammatory stress induced by TNF-α, IL-6, and IL-17 triggers derangement of BBB in NDs, thereby facilitate passage of other pro-inflammatory and inflammatory cytokines, and activated immune cells into the CNS.⁶⁹ Therefore, peripherally activated immune cells in hyperuricemia and gout can cross BBB leading to the development and progression of neuroinflammation.⁷⁰ Therefore, hyperuricemia-induced inflammation could the causal relationship in the induction and progression of NDs.

Brain tissue can generate uric acid during ischemia via neuronal xanthine oxidase. This process is associated with production of ROS causing neuronal injury and apoptosis.⁷¹ It has been reported that hyperuricemia is associated with silent brain infraction mainly in women.⁷¹ Thus, hyperuricemia increases brain oxidative stress which reduces hippocampal antioxidant enzymes such as superoxide dismutase (SOD).⁶⁵ Ischemic stroke is correlated with cognitive impairment.⁷² Therefore, hyperuricemia-induced cognitive impairment is mediated by oxidative stress and brain ischemic changes.

In upper limit hyperuricemia, uric acid acts as prooxidant augments free radical formation, and become more prooxidant through interaction with different oxidants such as peroxynitrite which cause lipid peroxidation.⁷³ Hydrophilic microenvironment created by lipid peroxidation attenuates the antioxidant effect of uric acid due to it hydrophilicity.⁷⁴ Therefore, uric acid antioxidant is ineffective against lipophilic radicals-induced lipid membrane peroxidation. In addition, uric acid can induce LDL oxidation in presence of lipid hydro peroxidase and copper (Cu⁺²) leading to mitochondrial dysfunction and oxidative stress.^73,74 Moreover, hyperuricemia can cause hippocampal oxidative stress and mitochondrial dysfunction which also triggers hippocampal inflammation in rats.⁷⁵ As well, uric acid promotes the expression of hippocampal NF-κB by inhibiting NF-κB inhibitor IκBα.⁷⁶ In this bargain, inhibition of uric acid synthesis by febuxostat can reduce markers of oxidative stress.⁷⁷

On the other hand, hyperuricemia can cause cerebral vascular injury which is a risk factor for vascular dementia and cognitive impairment.⁷⁸ Hyperuricemia-induced brain oxidative stress induces structural and functional deteriorations of neurons and cerebral vasculatures increasing risk of brain ischemia.⁷⁹ These changes promote the amyloid precursor protein (APP) processing toward amyloidogenic pathway to generate neurotoxic Aβ.⁸⁰ Hyperuricemia-induced endothelial dysfunction of cerebral vasculature impairs Aβ clearance across BBB.⁸¹ Besides, accumulated Aβ triggers oxidative stress and neuroinflammation by activating microglia and astrocytes.⁸² Therefore, there is a crosstalk between hyperuricemia and Aβ in the induction of oxidative stress and neuroinflammation. Preclinical finding demonstrated that incubation of SHSY5Y cells with uric acid potentiates the neurotoxic effect of Aβ by increasing the expression of expression of peroxisome proliferator activator receptor (PPAR).⁸³ Therefore, hyperuricemia may increase AD risk by inducing Aβ.⁸⁴ A cohort study showed that high uric acid is correlated with CSF tau protein and Aβ_1-42⁸⁴ suggesting the potential effect of hyperuricemia in AD neuropathology. As previously mentioned, that uric acid has ability to reduce iron accumulation in the SNpc however, a pilot study on 30 PD patients and 25 healthy controls showed that uric acid had no role in preventing iron accumulation in the SNpc.⁸⁵

Moreover, hyperuricemia is correlated with high risk of metabolic syndrome, as uric acid is positively correlated with circulating cholesterol, triglyceride, and glucose. Uric acid inhibits AMP-activated protein kinase (AMPK).⁸⁶ It has been suggested that metabolic syndrome increases risk of AD and other neurodegenerative diseases through induction of brain insulin resistance, neuroinflammation, mitochondrial dysfunction, and oxidative stress.⁸⁷ As well, uric acid through inhibition of AMPK induces inflammatory changes causing atherosclerosis which associated with vascular dementia and other neurodegenerative diseases.⁸⁸ Moreover, hyperuricemia exaggerates ALS neuropathology, and use of non-purine xanthine oxidase inhibitors such as febuxostat can attenuate ALS neuropathology by increasing the purine salvage pathway which reduces death of motor neurons in mouse ALS model.⁸⁹

Taken together, hyperuricemia and gout through induction of inflammation, oxidative stress and neuroinflammation may augment risk of NDs (Table 2).

TABLE 2 The detrimental role of hyperuricemia against the development of NDs.

Ref.	Type of the study	Findings
53	A preclinical	Hyperuricemia induces cognitive impairment in mice by inducing oxidative stress, release of TNF-α and the accumulation of Aβ
54	A case–control study	High serum uric acid is correlated with cognitive impairment and white matter atrophy
55	A prospective study	High basal level of serum uric acid is connected with cognitive decline and memory impairment
56	A case–control study	The relationship between serum uric acid and cognitive function is U shape in T2D patients
57,58	Case–control studies	Gout patients have small brain volume, and brain atrophy
61	A longitudinal study	Gout increases risk of AD and PD below the age of 60 years
62,64	Observational studies	Gout augments PD risk by 14%, and dementia risk by 15%
81	A preclinical	Hyperuricemia-induced endothelial dysfunction of cerebral vasculature impairs Aβ clearance across BBB
83	A preclinical	Uric acid potentiates the neurotoxic effect of Aβ by increasing the expression of PPAR
84	A cohort study	High uric acid is correlated with CSF tau protein and Aβ1-42
88	A preclinical	Uric acid through the inhibition of AMPK induces vascular dementia and other NDs
89	A preclinical	Febuxostat can attenuate ALS neuropathology by increasing the purine salvage pathway which reduces death of motor neurons in mouse ALS model

DISCUSSION

Finding of the present review illustrated that uric acid has protective effect against NDs by its antioxidant and anti-inflammatory effects, and detrimental effects by its prooxidant and pro-inflammatory effects (Figure 5).

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The relationship between hyperuricemia and NDs are conflicting, thus findings from many meta-analyses there are often heterogeneity. For example, cognitive function of patients with hyperuricemia or gout in cross-sectional or case–control studies was not evaluated or followed for long period.⁹⁰ Uric acid affects the cognitive functions differentially at different times, though data obtained from population-based was not determined baseline cognitive function variability.⁹¹ Importantly, most of selected patients with dementia does not depend on neuroimaging findings, but instead was mainly dependent on ICD9-CM codes which subjected to potential bias.⁹² In addition, comorbidities linked with gout or hyperuricemia such as metabolic syndrome, chronic kidney disease, atherosclerosis, dyslipidemia, and hypertension that often affect the pathogenesis of NDs were not evaluated.⁹³ These limitations may explain the conflicting outcomes concerning the relationship between hyperuricemia and NDs.

Despite the clinical helpful effects of uric acid against the development and progression of NDs, uric acid is not clinically used as it poorly soluble at physiological pH.⁹⁴ However, dietary supplement with uric acid precursor inosine can boost endogenous uric acid production that is effect against autoimmune diseases, PD and ALS.^95,96 Likewise, ATP supplements increase the production of endogenous uric acid.⁹⁷ Theoretically, xanthine oxidase activators or inhibition of intestinal uric acid excretion could be a novel pathway for increasing the production of uric acid and reducing uric acid excretion, respectively.⁹⁸ Preclinical findings revealed that increasing solubility of uric acid increase its antioxidant effect. For example, 1,7-dimehyl uric acid is highly soluble uric acid had a neuroprotective effect against ischemic stroke in mice.⁹⁹ Of interest, 1,7-dimehyl uric acid is the final metabolite of caffeine,¹⁰⁰ therefor caffeine and other methylxanthines have neuroprotective effects against NDs.¹⁰¹

Furthermore, medications used in the management of hyperuricemia and gout also had neuroprotective effects against NDs, allopurinol reduce NDs risk by 24%.¹⁰² It has been shown that allopurinol attenuates mitochondrial dysfunction in AD by inhibiting amyloid-binding alcohol dehydrogenase.¹⁰³ Lai et al.¹⁰⁴ showed no significant association between allopurinol use and PD risk. A meta-analysis of case–control studies revealed that prolong use of allopurinol reduces risk of dementia.¹⁰⁵ Moreover, xanthine oxidase inhibitors allopurinol and febuxostat comparatively reduce dementia risk.¹⁰⁶ These findings indicated the neuroprotective effects of xanthine oxidase inhibitors against NDs. Unfortunately, these medications were not estimated regarding effect of hyperuricemia on cognitive functions in patients with NDs.

Taken together, the relationship between uric acid and NDs risk still conflicting, and additional prospective studies with consideration of anti-hyperuricemia medications are warranted.

CONCLUSIONS

NDs are group of diseases affecting the CNS such as AD and PD characterized by progressive neurodegenerations in specific brain regions. Findings from different studies highlighted the neuroprotective role uric acid against the development and progression of AD and PD. Though, recent studies indicated that high level of uric acid may act as prooxidant causing oxidative stress and cognitive impairment. The neuroprotective effect of uric acid is mediated by mitigating oxidative stress-induced neurodegeneration. However, long-term effect of hyperuricemia predisposes for the development and progression of cognitive impairment by inducing oxidative stress, release of pro-inflammatory TNF-α, and accumulation of Aβ. Hyperuricemia-induced oxidative stress can induce brain ischemic changes and cerebral vascular injury which increase risk factor for vascular dementia and cognitive impairment. Moreover, hyperuricemia is correlated with high risk of metabolic syndrome which augment risk of NDs.

Furthermore, medications used in the management of hyperuricemia and gout also had neuroprotective effects against NDs, though these medications were not estimated regarding the effect of hyperuricemia on cognitive functions in patients with NDs. In summary, the relationship between uric acid and NDs risk are conflicting, and additional prospective concerning the effects of anti-hyperuricemia medications are reasonable.

AUTHOR CONTRIBUTIONS

Hayder M. Al-kuraishy, Ali I. Al-Gareeb, Athanasios Alexiou drafted the manuscript. Marios Papadakis, Mostafa M. Bahaa, Mohammed Alrouji, Mohammed S. Alshammari, Gaber El-Saber Batiha revised and edited the manuscript. All authors contributed to the editing of the manuscript, performed extensive proofreading of the manuscript. All authors have read and approved the final manuscript.

ACKNOWLEDGMENTS

The authors would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work.

FUNDING INFORMATION

Open access funding enabled and organized by Project DEAL. This work was supported by University of Written-Herdeck, Germany.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT

All data generated or analyzed during this study are included in this published article.

ETHICAL APPROVAL

Approval of the Research Protocol by an Institutional Reviewer Board: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study: N/A.

Animal Studies: N/A.

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