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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry


ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

Research Article

Relationship Between Oxidative Stress, Tau Level and Antioxidant Mechanisms of the KEAP-1/NRF-2/HO-1 in Children with Hydrocephalus

Author(s): Ahmet Guzelcicek*, Ismail Koyuncu, Ataman Gönel, Gulyara Cigdem and Mehmet Karadag

Volume 20, Issue 3, 2021

Published on: 28 December, 2020

Page: [282 - 289] Pages: 8

DOI: 10.2174/1871523019666201228111713

Price: $65


Background: Hydrocephalus is a complex neurologic disorder that has a widespread impact on the central nervous system and a multifactor disease which affects the CSF dynamics and causes severe neurological impairments in children. The pathophysiology of hydrocephalus is not fully understood. However, increasing evidence suggests that oxidative stress may be an important factor in the pathogenesis of hydrocephalus.

Objective: The purpose of this study is to investigate the relationship of the KEAP-1/NRF-2/HO-1 pathway, one of the main regulators of the antioxidant system in the hydrocephalus pathology, on oxidative stress and tau protein level.

Methods: The study included 32 patients with hydrocephalus and 32 healthy controls. KEAP-1, NRF-2, HO-1, TAU, and MPO levels are measured using ELISA method TAS, TOS, and Total THIOL colorimetric method.

Results: KEAP-1, TAS, and Total THIOL levels were found significantly lowerer in the hydrocephalus group than in the control group. Nevertheless, it was identified that in the hydrocephalus group that the NRF-2, HO-1, TAU, MPO, TOS, and OSI levels were significantly elevated.

Conclusion: In conclusion, although the KEAP-1/NRF-2/HO-1 pathway is activated in patients with hydrocephalus, it is identified that the antioxidant defense system is insufficient and ultimately leads to elevated oxidative stress. The elevation in the tau level may be an indicator of oxidative stress induced neurodegenerative damage.

Keywords: KEAP-1, NRF-2, HO-1, oxidative stress, hydrocephalus, TAU.

Graphical Abstract
Bondurant, C.P.; Jimenez, D.F. Epidemiology of cerebrospinal fluid shunting. Pediatr. Neurosurg., 1995, 23(5), 254-258.
[] [PMID: 8688350]
Lam, S.; Harris, D.; Rocque, B.G.; Ham, S.A. Pediatric endoscopic third ventriculostomy: a population-based study. J. Neurosurg. Pediatr., 2014, 14(5), 455-464.
[] [PMID: 25238625]
Del Bigio, M.R. Neuropathology and structural changes in hydrocephalus. Dev. Disabil. Res. Rev., 2010, 16(1), 16-22.
[] [PMID: 20419767]
McAllister, J.P., II; Williams, M.A.; Walker, M.L.; Kestle, J.R.; Relkin, N.R.; Anderson, A.M.; Gross, P.H.; Browd, S.R. Hydrocephalus symposium expert panel. An update on research priorities in hydrocephalus: Overview of the third National Institutes of Health-sponsored symposium “Opportunities for hydrocephalus research: Pathways to better outcomes”. J. Neurosurg., 2015, 123(6), 1427-1438.
[] [PMID: 26090833]
Williams, M.A.; McAllister, J.P.; Walker, M.L.; Kranz, D.A.; Bergsneider, M.; Del Bigio, M.R.; Fleming, L.; Frim, D.M.; Gwinn, K.; Kestle, J.R.; Luciano, M.G.; Madsen, J.R.; Oster-Granite, M.L.; Spinella, G. Priorities for hydrocephalus research: report from a National Institutes of Health-sponsored workshop. J. Neurosurg., 2007, 107(5)(Suppl.), 345-357.
[PMID: 18459897]
Guerra, M.M.; Henzi, R.; Ortloff, A.; Lichtin, N.; Vío, K.; Jiménez, A.J.; Dominguez-Pinos, M.D.; González, C.; Jara, M.C.; Hinostroza, F.; Rodríguez, S.; Jara, M.; Ortega, E.; Guerra, F.; Sival, D.A.; den Dunnen, W.F.; Pérez-Fígares, J.M.; McAllister, J.P.; Johanson, C.E.; Rodríguez, E.M. Cell junction pathology of neural stem cells is associated with ventricular zone disruption, hydrocephalus, and abnormal neurogenesis. J. Neuropathol. Exp. Neurol., 2015, 74(7), 653-671.
[] [PMID: 26079447]
Aojula, A.; Botfield, H.; McAllister, J.P., II; Gonzalez, A.M.; Abdullah, O.; Logan, A.; Sinclair, A. Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile communicating hydrocephalus. Fluids Barriers CNS, 2016, 13(1), 9.
[] [PMID: 27246837]
McAllister, J.P., II Seminars in Fetal and Neonatal Medicine; Elsevier, 2012, Vol. 17, pp. 285-294.
Rocha Catalão, C.H.; Leme Correa, D.A.; Bernardino Garcia, C.A.; dos Santos, A.C.; Garrido Salmon, C.E.; Alves Rocha, M.J.; da Silva Lopes, L. Pre- and postshunting magnetization transfer ratios are in accordance with neurological and behavioral changes in hydrocephalic immature rats. Dev. Neurosci., 2014, 36(6), 520-531.
[] [PMID: 25342396]
Drake, J.M. The surgical management of pediatric hydrocephalus. Neurosurgery, 2008, 62(2), 633-40.
Grubb, R.L., Jr; Raichle, M.E.; Phelps, M.E.; Ratcheson, R.A. Effects of increased intracranial pressure on cerebral blood volume, blood flow, and oxygen utilization in monkeys. J. Neurosurg., 1975, 43(4), 385-398.
[] [PMID: 808593]
Yeom, K.W.; Lober, R.M.; Alexander, A.; Cheshier, S.H.; Edwards, M.S. Hydrocephalus decreases arterial spin-labeled cerebral perfusion. AJNR Am. J. Neuroradiol., 2014, 35(7), 1433-1439.
[] [PMID: 24651817]
Meng, H.; Guo, J.; Wang, H.; Yan, P.; Niu, X.; Zhang, J. Erythropoietin activates Keap1-Nrf2/ARE pathway in rat brain after ischemia. Int. J. Neurosci., 2014, 124(5), 362-368.
[] [PMID: 24063261]
Shih, A.Y.; Johnson, D.A.; Wong, G.; Kraft, A.D.; Jiang, L.; Erb, H.; Johnson, J.A.; Murphy, T.H. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci., 2003, 23(8), 3394-3406.
[] [PMID: 12716947]
Sireesh, D.; Ganesh, M-R.; Dhamodharan, U.; Sakthivadivel, M.; Sivasubramanian, S.; Gunasekaran, P.; Ramkumar, K.M. Role of pterostilbene in attenuating immune mediated devastation of pancreatic beta cells via Nrf2 signaling cascade. J. Nutr. Biochem., 2017, 44, 11-21.
[] [PMID: 28343084]
Bhakkiyalakshmi, E.; Sireesh, D.; Rajaguru, P.; Paulmurugan, R.; Ramkumar, K.M. The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes. Pharmacol. Res., 2015, 91, 104-114.
[] [PMID: 25447793]
Cakirca, G.; Manav, V.; Celik, H.; Saracoglu, G.; Yetkin, E.N. Effects of anxiety and depression symptoms on oxidative stress in patients with alopecia areata. Postępy. Dermatol. Allergo., 2020, 37(3), 412-416.
Tonelli, C.; Chio, I.I.C.; Tuveson, D.A. Transcriptional Regulation by Nrf2. Antioxid. Redox Signal., 2018, 29(17), 1727-1745.
[] [PMID: 28899199]
Volpon Santos, M.; da Silva Lopes, L.; Machado, H.R.; Santos de Oliveira, R. Behavioral and biochemical features of the course and surgical treatment of experimental obstructive hydrocephalus in young rats. Dev. Neurosci., 2019, 41(1-2), 34-43.
[] [PMID: 30999305]
Sendrowski, K.; Sobaniec, W.; Sobaniec-Lotowska, M.E.; Lewczuk, P. S-100 protein as marker of the blood-brain barrier disruption in children with internal hydrocephalus and epilepsy-A preliminary study. Rocz. Akad. Med. Bialymst., 2004, 49(49)(Suppl. 1), 236-238.
[PMID: 15638435]
Naureen, I.; Waheed, K.A.; Rathore, A.W.; Victor, S.; Mallucci, C.; Goodden, J.R.; Chohan, S.N.; Miyan, J.A. Fingerprint changes in CSF composition associated with different aetiologies in human neonatal hydrocephalus: Glial proteins associated with cell damage and loss. Fluids Barriers CNS, 2013, 10(1), 34.
[] [PMID: 24351234]
Jeppsson, A.; Zetterberg, H.; Blennow, K.; Wikkelsø, C. Idiopathic normal-pressure hydrocephalus: pathophysiology and diagnosis by CSF biomarkers. Neurology, 2013, 80(15), 1385-1392.
[] [PMID: 23486875]
Tullberg, M.; Blennow, K.; Månsson, J-E.; Fredman, P.; Tisell, M.; Wikkelsö, C. Cerebrospinal fluid markers before and after shunting in patients with secondary and idiopathic normal pressure hydrocephalus. Cerebrospinal Fluid Res., 2008, 5(1), 9.
[] [PMID: 18439296]
Schmitz, T.; Felderhoff-Mueser, U.; Sifringer, M.; Groenendaal, F.; Kampmann, S.; Heep, A. Expression of soluble Fas in the cerebrospinal fluid of preterm infants with posthemorrhagic hydrocephalus and cystic white matter damage. J. Perinat. Med., 2011, 39(1), 83-88.
[] [PMID: 20954855]
Merhar, S. Biomarkers in neonatal posthemorrhagic hydrocephalus. Neonatology, 2012, 101(1), 1-7.
[] [PMID: 21791933]
Gopal, S.C.; Pandey, A.; Das, I.; Gangopadhyay, A.N.; Upadhyaya, V.D.; Chansuria, J.P.; Singh, T.B. Comparative evaluation of 5-HIAA (5-hydroxy indoleacetic acid) and HVA (homovanillic acid) in infantile hydrocephalus. Child's Nervous System, 2008, 24(6), 713-716.
[] [PMID: 18075745]
Gopal, S.C.; Sharma, V.; Chansuria, J.P.; Gangopadhyaya, A.N.; Singh, T.B. Serotonin and 5-hydroxy indole acetic acid in infantile hydrocephalus. Pediatr. Surg. Int., 2007, 23(6), 571-574.
[] [PMID: 17380338]
Tullberg, M.; Blennow, K.; Månsson, J.E.; Fredman, P.; Tisell, M.; Wikkelsö, C. Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus. Eur. J. Neurol., 2007, 14(3), 248-254.
[] [PMID: 17355543]
Huang, H.; Yang, J.; Luciano, M.; Shriver, L.P. Longitudinal metabolite profiling of cerebrospinal fluid in normal pressure hydrocephalus links brain metabolism with exercise-induced VEGF production and clinical outcome. Neurochem. Res., 2016, 41(7), 1713-1722.
[] [PMID: 27084769]
Sival, D.A.; Felderhoff-Müser, U.; Schmitz, T.; Hoving, E.W.; Schaller, C.; Heep, A. Neonatal high pressure hydrocephalus is associated with elevation of pro-inflammatory cytokines IL-18 and IFNgamma in cerebrospinal fluid. Cerebrospinal Fluid Res., 2008, 5(1), 21.
[] [PMID: 19117508]
Zhang, S.; Chen, D.; Huang, C.; Bao, J.; Wang, Z. Expression of HGF, MMP-9 and TGF-β1 in the CSF and cerebral tissue of adult rats with hydrocephalus. Int. J. Neurosci., 2013, 123(6), 392-399.
[] [PMID: 23270462]
Douglas, M.R.; Daniel, M.; Lagord, C.; Akinwunmi, J.; Jackowski, A.; Cooper, C.; Berry, M.; Logan, A. High CSF transforming growth factor β levels after subarachnoid haemorrhage: Association with chronic communicating hydrocephalus. J. Neurol. Neurosurg. Psychiatry, 2009, 80(5), 545-550.
[] [PMID: 19066194]
Blennow, K.; Hardy, J.; Zetterberg, H. The neuropathology and neurobiology of traumatic brain injury. Neuron, 2012, 76(5), 886-899.
[] [PMID: 23217738]
Limbrick, D.D., Jr; Baksh, B.; Morgan, C.D.; Habiyaremye, G.; McAllister, J.P., II; Inder, T.E.; Mercer, D.; Holtzman, D.M.; Strahle, J.; Wallendorf, M.J.; Morales, D.M. Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus. PLoS One, 2017, 12(2), e0172353.
[] [PMID: 28212403]
Ames, B.N.; Shigenaga, M.K.; Hagen, T.M. Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA, 1993, 90(17), 7915-7922.
[] [PMID: 8367443]
Evans, P.H. Free radicals in brain metabolism and pathology. Br. Med. Bull., 1993, 49(3), 577-587.
[] [PMID: 8221024]
Halliwell, B. Reactive oxygen species and the central nervous system. J. Neurochem., 1992, 59(5), 1609-1623.
[] [PMID: 1402908]
In; Watson, B.D. Progress in Brain ResearchElsevier, 1993, 96, pp. 69-95.
Jabs, T. Reactive oxygen intermediates as mediators of programmed cell death in plants and animals. Biochem. Pharmacol., 1999, 57(3), 231-245.
[] [PMID: 9890550]
Poyton, R.O.; Ball, K.A.; Castello, P.R. Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol. Metab., 2009, 20(7), 332-340.
[] [PMID: 19733481]
Fridovich, I. The biology of oxygen radicals. Science, 1978, 201(4359), 875-880.
[] [PMID: 210504]
Reuter, S.; Gupta, S.C.; Chaturvedi, M.M.; Aggarwal, B.B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med., 2010, 49(11), 1603-1616.
[] [PMID: 20840865]
Dreger, H.; Westphal, K.; Wilck, N.; Baumann, G.; Stangl, V.; Stangl, K.; Meiners, S. Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc. Res., 2010, 85(2), 395-403.
[] [PMID: 19679681]
Kensler, T.W.; Wakabayashi, N.; Biswal, S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol., 2007, 47, 89-116.
[] [PMID: 16968214]
Kang, M-I.; Kobayashi, A.; Wakabayashi, N.; Kim, S-G.; Yamamoto, M. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc. Natl. Acad. Sci. USA, 2004, 101(7), 2046-2051.
[] [PMID: 14764898]
Adams, J.; Kelso, R.; Cooley, L. The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol., 2000, 10(1), 17-24.
[] [PMID: 10603472]
Dinkova-Kostova, A.T.; Holtzclaw, W.D.; Wakabayashi, N. Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry, 2005, 44(18), 6889-6899.
[] [PMID: 15865434]
Velichkova, M.; Hasson, T. Keap1 in adhesion complexes. Cell Motil. Cytoskeleton, 2003, 56(2), 109-119.
[] [PMID: 14506708]
Tu, W.; Wang, H.; Li, S.; Liu, Q.; Sha, H. The anti-inflammatory and anti-oxidant mechanisms of the Keap1/Nrf2/ARE signaling pathway in chronic diseases. Aging Dis., 2019, 10(3), 637-651.
[] [PMID: 31165007]
Cleveland, D.W.; Hwo, S-Y.; Kirschner, M.W. Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J. Mol. Biol., 1977, 116(2), 227-247.
[] [PMID: 146092]
Su, B.; Wang, X.; Zheng, L.; Perry, G.; Smith, M.A.; Zhu, X. Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim. Biophys. Acta, 2010, 1802(1), 135-142.
[] [PMID: 19799998]
Beharry, C.; Cohen, L.S.; Di, J.; Ibrahim, K.; Briffa-Mirabella, S.; Alonso, Adel.C. Tau-induced neurodegeneration: mechanisms and targets. Neurosci. Bull., 2014, 30(2), 346-358.
[] [PMID: 24733656]
Wolfe, M.S. The role of tau in neurodegenerative diseases and its potential as a therapeutic target. Scientifica, 2012, 796024.
Gendron, T.F.; Petrucelli, L. The role of tau in neurodegeneration. Mol. Neurodegener., 2009, 4(1), 13.
[] [PMID: 19284597]

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