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Preclinical validation of a novel oral Edaravone formulation for treatment of frontotemporal dementia

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Abstract

Oxidative stress is a key factor in the pathogenesis of several neurodegenerative disorders and is involved in the accumulation of amyloid beta plaques and Tau inclusions. Edaravone (EDR) is a free radical scavenger that is approved for motor neuron disease and acute ischemic stroke. EDR alleviates pathologies and cognitive impairment of AD via targeting multiple key pathways in transgenic mice. Herein, we aimed to study the effect of EDR on Tau pathology in P301L mice; an animal model of frontotemporal dementia (FTD), at two age time points representing the early and late stages of the disease. A novel EDR formulation was utilized in the study and the drug was delivered orally in drinking water for 3 months. Then, behavioral tests were conducted followed by animal sacrifice and brain dissection. Treatment with EDR improved the reference memory and accuracy in the probe trial as evaluated in Morris water maze, as well as novel object recognition and significantly alleviated motor deficits in these mice. EDR also reduced the levels of 4-hydroxy-2-nonenal and 3-nitrotyrosine adducts. In addition, immunohistochemistry showed that EDR reduced tau phosphorylation and neuroinflammation and partially rescued neurons against oxidative neurotoxicity. Moreover, EDR attenuated downstream pathologies involved in Tau hyperphosphorylation. These results suggest that EDR may be a potential therapeutic agent for the treatment of FTD.

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References:

  • Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Bennett DA (2006) Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease. Arch Neurol 63:1763–1769

    Article  PubMed  Google Scholar 

  • Ahsan H (2013) 3-Nitrotyrosine: a biomarker of nitrogen free radical species modified proteins in systemic autoimmunogenic conditions. Hum Immunol 74:1392–1399

    Article  CAS  PubMed  Google Scholar 

  • Alavi Naini SM, Soussi-Yanicostas N (2015) Tau hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies? Oxid Med Cell Longev 2015:151979

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Albers DS, Augood SJ, Martin DM et al (1999) Evidence for oxidative stress in the subthalamic nucleus in progressive supranuclear palsy. J Neurochem 73:881–884

    Article  CAS  PubMed  Google Scholar 

  • Banno M, Mizuno T, Kato H et al (2005) The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia. Neuropharmacology 48:283–290

    Article  CAS  PubMed  Google Scholar 

  • Barber SC, Shaw PJ (2010) Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radical Biol Med 48:629–641

    Article  CAS  Google Scholar 

  • Burrell JR, Kiernan MC, Vucic S, Hodges JR (2011) Motor Neuron dysfunction in frontotemporal dementia. Brain 134:2582–2594

    Article  PubMed  Google Scholar 

  • Cente M, Filipcik P, Pevalova M, Novak M (2006) Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J Neurosci 24:1085–1090

    Article  PubMed  Google Scholar 

  • Cherry JD, Tripodis Y, Alvarez VE et al (2016) Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta Neuropathol Commun 4:112–112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cook C, Dunmore JH, Murray ME et al (2014) Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia. Neurobiol Aging 35:1769–1777

    Article  CAS  PubMed  Google Scholar 

  • Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695

    Article  CAS  PubMed  Google Scholar 

  • Dalleau S, Baradat M, Guéraud F, Huc L (2013) Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance. Cell Death Differ 20:1615–1630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • David DC, Hauptmann S, Scherping I et al (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 280:23802–23814

    Article  CAS  PubMed  Google Scholar 

  • Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB (2007) Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 117:236–245

    Article  CAS  PubMed  Google Scholar 

  • DuBoff B, Götz J, Feany MB (2012) Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 75:618–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dumont M, Stack C, Elipenahli C et al (2011) Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. FASEB J 25:4063–4072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dutschmann M, Menuet C, Stettner GM et al (2010) Upper airway dysfunction of Tau-P301L mice correlates with tauopathy in midbrain and ponto-medullary brainstem nuclei. J Neurosci 30:1810–1821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elipenahli C, Stack C, Jainuddin S et al (2012) Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice. J Alzheimers Dis 28:173–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng S, Yang Q, Liu M, et al. (2011) Edaravone for acute ischaemic stroke. Cochrane Database Syst Rev, Cd007230

  • Gabbita SP, Scheff SW, Menard RM et al (2005) Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury. J Neurotrauma 22:83–94

    Article  PubMed  Google Scholar 

  • Gamblin TC, King ME, Kuret J, Berry RW, Binder LI (2000) Oxidative regulation of fatty acid-induced tau polymerization. Biochemistry 39:14203–14210

    Article  CAS  PubMed  Google Scholar 

  • Goedert M, Hasegawa M, Jakes R et al (1997) Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett 409:57–62

    Article  CAS  PubMed  Google Scholar 

  • Good PF, Werner P, Hsu A, Olanow CW, Perl DP (1996) Evidence of neuronal oxidative damage in Alzheimer’s disease. Am J Pathol 149:21–28

    CAS  PubMed  PubMed Central  Google Scholar 

  • Götz J, Chen F, Barmettler R, Nitsch RM (2001) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276:529–534

    Article  PubMed  Google Scholar 

  • Götz J, Halliday G, Nisbet R (2019) Molecular Pathogenesis of the Tauopathies. Ann Rev Pathol 14:239

    Article  CAS  Google Scholar 

  • Götz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544

    Article  PubMed  CAS  Google Scholar 

  • Hampton AL, Hish GA, Aslam MN et al (2012) Progression of ulcerative dermatitis lesions in C57BL/6Crl mice and the development of a scoring system for dermatitis lesions. J Am Assoc Lab Anim Sci 51:586–593

    CAS  PubMed  PubMed Central  Google Scholar 

  • Haque MM, Murale DP, Kim YK, Lee J-S (2019) Crosstalk between oxidative stress and tauopathy. Int J Mol Sci 20:1959

    Article  CAS  PubMed Central  Google Scholar 

  • Hernandez F, Lucas JJ, Avila J (2013) GSK3 and tau: two convergence points in Alzheimer’s disease. J Alzheimers Dis 33(Suppl 1):S141-144

    PubMed  Google Scholar 

  • Jiao S-S, Yao X-Q, Liu Y-H et al (2015) Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits. Proc Natl Acad Sci U S A 112:5225–5230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kashon ML, Ross GW, O’Callaghan JP et al (2004) Associations of cortical astrogliosis with cognitive performance and dementia status. J Alzheimers Dis 6:595–604

    Article  PubMed  Google Scholar 

  • Köhler C, Dinekov M, Götz J (2013) Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice. Neurobiol Aging 34:1369–1379

    Article  PubMed  CAS  Google Scholar 

  • Lee K-Y, Koh S-H, Noh MY et al (2007) Glycogen synthase kinase-3β activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells. Brain Res 1129:89–99

    Article  CAS  PubMed  Google Scholar 

  • Lewis J, McGowan E, Rockwood J et al (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405

    Article  CAS  PubMed  Google Scholar 

  • Lovell MA, Xiong S, Xie C, Davies P, Markesbery WR (2004) Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. J Alzheimers Dis 6:659–671

    Article  CAS  PubMed  Google Scholar 

  • Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival*. J Cell Physiol 192:1–15

    Article  CAS  PubMed  Google Scholar 

  • Mecocci P, Polidori MC (2012a) Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim Biophys Acta 1822:631–638

    Article  CAS  PubMed  Google Scholar 

  • Mecocci P, Polidori MC (2012b) Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim Biophys Acta 1822:631–638

    Article  CAS  PubMed  Google Scholar 

  • Mondragón-Rodríguez S, Perry G, Zhu X et al (2013) Phosphorylation of tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: implications for Alzheimer’s disease. Oxid Med Cell Longev 2013:940603–940603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683

    Article  CAS  PubMed  Google Scholar 

  • Nakashima H, Ishihara T, Yokota O et al (2004) Effects of alpha-tocopherol on an animal model of tauopathies. Free Radical Biol Med 37:176–186

    Article  CAS  Google Scholar 

  • National Health and Medical Research Council (2013) Australian code for the care and use of animals for scientific purposes, 8 edn. NHMRC, Canberra

    Google Scholar 

  • Onyike CU, Diehl-Schmid J (2013) The epidemiology of frontotemporal dementia. Int Rev Psychiatry (abingdon, England) 25:130–137

    Article  Google Scholar 

  • Orr ME, Sullivan AC, Frost B (2017) A brief overview of tauopathy: causes, consequences, and therapeutic strategies. Trends Pharmacol Sci 38:637–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parikh A, Kathawala K, Li J et al (2018a) Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of efficacy against behavior deficits and safety in Alzheimer’s disease model. Drug Des Devel Ther 12:2111–2128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parikh A, Kathawala K, Tan CC, Garg S, Zhou X-F (2018b) Self-nanomicellizing solid dispersion of edaravone: part I - oral bioavailability improvement. Drug Des Devel Ther 12:2051–2069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pennanen L, Wolfer DP, Nitsch RM, Götz J (2006) Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic mice. Genes Brain Behav 5:369–379

    Article  CAS  PubMed  Google Scholar 

  • Pérez M, Cuadros R, Smith MA, Perry G, Avila J (2000) Phosphorylated, but not native, tau protein assembles following reaction with the lipid peroxidation product, 4-hydroxy-2-nonenal. FEBS Lett 486:270–274

    Article  PubMed  Google Scholar 

  • Poorkaj P, Bird TD, Wijsman E et al (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825

    Article  CAS  PubMed  Google Scholar 

  • Rajasekar N, Dwivedi S, Tota SK et al (2013) Neuroprotective effect of curcumin on okadaic acid induced memory impairment in mice. Eur J Pharmacol 715:381–394

    Article  CAS  PubMed  Google Scholar 

  • Ramsden M, Kotilinek L, Forster C et al (2005) Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25:10637–10647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rong W-T, Lu Y-P, Tao Q et al (2014) Hydroxypropyl-sulfobutyl-β-cyclodextrin improves the oral bioavailability of Edaravone by modulating drug efflux pump of enterocytes. J Pharm Sci 103:730–742

    Article  CAS  PubMed  Google Scholar 

  • Rudenko LK, Wallrabe H, Periasamy A et al (2019) Intraneuronal tau misfolding induced by extracellular amyloid-β oligomers. J Alzheimers Dis 71:1125–1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sancheti H, Kanamori K, Patil I et al (2014) Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer’s disease: a 13C NMR study. J Cereb Blood Flow Metab 34:288–296

    Article  CAS  PubMed  Google Scholar 

  • Shamma RN, Basha M (2013) Soluplus®: A novel polymeric solubilizer for optimization of Carvedilol solid dispersions: Formulation design and effect of method of preparation. Powder Technol 237:406–414

    Article  CAS  Google Scholar 

  • Sies H (1997) Oxidative stress: oxidants and antioxidants. Exp Physiol 82:291–295

    Article  CAS  PubMed  Google Scholar 

  • Silva MC, Haggarty SJ (2020) Tauopathies: deciphering disease mechanisms to develop effective therapies. Int J Mol Sci 21:8948

    Article  CAS  PubMed Central  Google Scholar 

  • Sinha M, Hk A, Juyal R et al (2009) Edaravone in acute ischemic stroke, an Indian experience. Neurol Asia 14:7–10

    Google Scholar 

  • Smith CD, Carney JM, Starke-Reed PE et al (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci U S A 88:10540–10543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stadtman ER (1992) Protein oxidation and aging. Science 257:1220–1224

    Article  CAS  PubMed  Google Scholar 

  • Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow E-M (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156:1051–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su B, Wang X, Nunomura A et al (2008) Oxidative stress signaling in Alzheimer’s disease. Curr Alzheimer Res 5:525–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subbarao KV, Richardson JS, Ang LC (1990) Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro. J Neurochem 55:342–345

    Article  CAS  PubMed  Google Scholar 

  • Thangavel R, Stolmeier D, Yang X, Anantharam P, Zaheer A (2012) Expression of glia maturation factor in neuropathological lesions of Alzheimer’s disease. Neuropathol Appl Neurobiol 38:572–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Jiang Q, Chu J et al (2013) Expression of tau40 induces activation of cultured rat microglial cells. PLoS ONE 8:e76057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17:5–21

    Article  PubMed  CAS  Google Scholar 

  • Watanabe K, Tanaka M, Yuki S, Hirai M, Yamamoto Y (2018) How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Clin Biochem Nutr 62:20–38

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T, Tahara M, Todo S (2008) The novel antioxidant Edaravone: from bench to bedside. Cardiovasc Ther 26:101–114

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T, Yuki S, Egawa M, Nishi H (1994) Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions. J Pharmacol Exp Ther 268:1597–1604

    CAS  PubMed  Google Scholar 

  • Wolf A, Bauer B, Abner EL, Ashkenazy-Frolinger T, Hartz AM (2016) A comprehensive behavioral test battery to assess learning and memory in 129S6/Tg2576 mice. PLoS ONE 11:e0147733

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yamamoto Y, Kuwahara T, Watanabe K, Watanabe K (1996) Antioxidant activity of 3-methyl-1-phenyl-2-pyrazolin-5-one. Redox Rep 2:333–338

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto T, Yuki S, Watanabe T et al (1997) Delayed neuronal death prevented by inhibition of increased hydroxyl radical formation in a transient cerebral ischemia. Brain Res 762:240–242

    Article  CAS  PubMed  Google Scholar 

  • Yarchoan M, Toledo JB, Lee EB et al (2014) Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol 128:679–689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida H, Yanai H, Namiki Y et al (2006) Neuroprotective effects of Edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev 12:9–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshino H (2019) Edaravone for the treatment of amyotrophic lateral sclerosis. Expert Rev Neurother 19:185–193

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge the support provided to S. Kelliny by Commonwealth Research and Training scholarship and Egyptian Ministry of Higher Education. We would like to thank Mr. Andrew Beck for suggestions regarding histological techniques and imaging. The authors would also like to acknowledge H Md Morshed Alam (BASF Australia Ltd) for providing samples of Soluplus, and Suzhou Auzone Biotech for the Edaravone formulation.

Funding

This study was supported by National Health and Medical Research Council (NHMRC) Grants (1020567, 1021409) and supporting Grant from the University of South Australia.

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Authors and Affiliations

  1. Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia

    Sally Kelliny, Larisa Bobrovskaya & Xin-Fu Zhou

  2. Department of Neurology, The Second Affiliated Hospital, Kunming Medical University, Kunming, Yunnan, China

    Jing Xiong

  3. Faculty of Pharmacy, Assiut University, Assiut, Egypt

    Sally Kelliny

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  1. Sally Kelliny
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  4. Xin-Fu Zhou
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Contributions

LB and XFZ contributed to the study conception and design. Material preparation, experiments, data collection and analysis were performed by SK. JX collaborated in animal studies. The first draft of the manuscript was written by SK and all authors commented on previous versions of the manuscript. LB and XFZ supervised the study. All the authors reviewed and approved the final version of the manuscript submitted.

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Correspondence to Xin-Fu Zhou.

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Conflict of interest

XFZ is one of the inventors of Chinese patent 200610149832.9. The authors report no other conflicts of interest in this work.

Ethical approval

All procedures were compliant with the approved protocol (U17-14, U13-18) from Animal Ethics Committee of the University of South Australia and the South Australia animal welfare act and the “Australian code of practice and use of animals for scientific purposes”.

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Kelliny, S., Xiong, J., Bobrovskaya, L. et al. Preclinical validation of a novel oral Edaravone formulation for treatment of frontotemporal dementia. Neurotox Res 39, 1689–1707 (2021). https://doi.org/10.1007/s12640-021-00405-2

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