Uric acid |
Antioxidant and pro-oxidant effects, white matter atrophy, and cerebral ischemic burden. Uric acid is a major alarmin that induces pro-inflammatory cytokine expression and secretion, as well as inflammation; the underlying mechanism for these functions is the activation of the nuclear factor-κ B by toll-like receptor 4. This response was activated more in neurons than in glial cells when rat hippocampi were studied. The promotion of gliosis has also been observed. Uric acid is also associated with atherosclerosis, endothelial and cardiovascular disease burden, microvascular renal disease, glomerular hypertension, glomerulosclerosis, and renal interstitial fibrosis. 2929 Verhaaren BF, Vernooij MW, Dehghan A, Vrooman HA, de Boer R, Hofman A, et al. The relation of uric acid to brain atrophy and cognition: the Rotterdam Scan Study. Neuroepidemiology 2013;41:29-34. 3030 Schretlen DJ, Inscore AB, Vannorsdall TD, Kraut M, Pearlson GD, Gordon B, et al. Serum uric acid and brain ischemia in normal elderly adults. Neurology 2007;69:1418-23. 3232 Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 2008;27:608-19. 6464 Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21. 6565 Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007;81:1-5. 6666 Shao X, Lu W, Gao F, Li D, Hu J, Li Y, et al. Uric Acid Induces Cognitive Dysfunction through Hippocampal Inflammation in Rodents and Humans. J Neurosci 2016;36:10990-1005.
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Indoxyl sulphate and p-cresyl sulphate |
Direct neurotoxicity of indoxyl sulphate is suggested, but not proven. Indoxyl sulphate possibly causes a disruption of the brain efflux transport systems. Some of the transporters found in brain capillary endothelium are the same secretory transport molecules found in the basolateral membrane of proximal tubular cells; for instance, the organic anion transporter 3 (OAT3). Indoxyl sulphate was found to accumulate in uremic patients’ brains. Indoxyl sulphate also causes nephrotoxic renal fibrosis through the accumulation in renal tubular cells, production of free radicals, inflammation, endothelial cell dysfunction, endothelial and proximal tubular cell senescence, atherosclerosis, and the disruption of rhythmicity regulation of clock genes (rPer2). 2626 Watanabe K, Watanabe T, Nakayama M. Cerebro-renal interactions: impact of uremic toxins on cognitive function. Neurotoxicology 2014;44:184-93. 6767 Iwata K, Watanabe H, Morisaki T, Matsuzaki T, Ohmura T, Hamada A, et al. Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure. Pharm Res 2007;24:662-71. 6868 Sirich TL, Meyer TW, Gondouin B, Brunet P, Niwa T. Protein-bound molecules: a large family with a bad character. Semin Nephrol 2014;34:106-17.
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Homocysteine (HCy) |
HCy increases oxidative stress, DNA damage, induction of apoptosis, production of homocysteic acid, excitotoxicity (mediated by NMDA glutamate receptor activation), white matter hyperintensities, cerebrovascular disease, and brain atrophy. Hyperhomocysteinemia is linked to cerebral microvascular rarefaction and dysfunction of the methylation of DNA, proteins, and phospholipids due to the inhibition of methyltransferase. This can lead toabnormal epigenetic regulation. Superoxide and hydrogen peroxide are formed by the oxidation of homocysteine, whose increased levels could cause a reduction in glutathione peroxidase activity and antioxidant potentials. Hyperhomocysteinemia also seems to cause alterations in the monoamine neurotransmitter system through mechanisms involving the inhibition of methyltransferase reactions and changes in the cellular redox state. Involving these same mechanisms, hyperhomocysteinemia also promotes the reduction of brain-derived neurotrophic factor (BDNF) levels in cerebrospinal fluid. BDNF is a protein related to cell maintenance, plasticity, growth and death. Hyperhomocysteinaemia also causes: endothelial dysfunction, prothrombogenic activity and cardiovascular disease. 1313 Lipton SA, Kim WK, Choi YB, Kumar S, D'Emilia DM, Rayudu PV, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 1997;94:5923-8. 1818 Fassbender K, Mielke O, Bertsch T, Nafe B, Fröschen S, Hennerici M. Homocysteine in cerebral macroangiography and microangiopathy. Lancet 1999;353:1586-7. 1919 Wright CB, Paik MC, Brown TR, Stabler SP, Allen RH, Sacco RL, et al. Total homocysteine is associated with white matter hyperintensity volume: the Northern Manhattan Study. Stroke 2005;36:1207-11. 2626 Watanabe K, Watanabe T, Nakayama M. Cerebro-renal interactions: impact of uremic toxins on cognitive function. Neurotoxicology 2014;44:184-93. 6969 Sachdev PS. Homocysteine and brain atrophy. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1152-61. 7070 Gao L, Zeng XN, Guo HM, Wu XM, Chen HJ, Di RK, et al. Cognitive and neurochemical alterations in hyperhomocysteinemic rat. Neurol Sci 2012;33:39-43.
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Interleukin 1-β and interleukin 6 |
These interleukins cause brain inflammation, particularly through microglial cells and astrocytes; DNA damage; oxidative stress; the up-regulation of glutamate resulting in excitotoxicity; and brain and systemic aging-related changes. 2626 Watanabe K, Watanabe T, Nakayama M. Cerebro-renal interactions: impact of uremic toxins on cognitive function. Neurotoxicology 2014;44:184-93. 5151 Dugan LL, Ali SS, Shekhtman G, Roberts AJ, Lucero J, Quick KL, et al. IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase. PLoS One 2009;4:e5518.
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Parathyroid hormone (PTH) |
PTH promotes mineral bone disorder, metastatic calcification, increased brain circulating and neuronal cytosol calcium levels causing changing in brain function, the induction of apoptosis due to calcium overloading, reduced regional cerebral blood flow, and somatic, behavioural and motor abnormalities. 2626 Watanabe K, Watanabe T, Nakayama M. Cerebro-renal interactions: impact of uremic toxins on cognitive function. Neurotoxicology 2014;44:184-93. 5959 Lourida I, Thompson-Coon J, Dickens CM, Soni M, Kuźma E, Kos K, et al. Parathyroid hormone, cognitive function and dementia: a systematic review. PLoS One 2015;10:e0127574.
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