Skip to main content

Advertisement

Log in

Edaravone Prevents Neurotoxicity of Mutant L166P DJ-1 in Parkinson’s Disease

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstracts

Parkinson's disease (PD), which is estimated to affect approximately 1 % of the population over the age of 65, is the second most common neurodegenerative disorder after Alzheimer’s disease. It was reported that pathogenic mutations in DJ-1 lead to autosomal recessive early-onset familial Parkinsonism. The L166P mutant of DJ-1 is the most commonly studied loss-of-function mutation in early onset familial PD, but the underlying mechanisms are still unknown. Edaravone is a powerful free radical scavenger used in clinical treatment for cerebral ischemic stroke. In the present study, we investigated the effects of edaravone on the neurotoxicity in PD-induced isoforms of DJ-1 containing the mutation L166P. Our results indicated that edaravone was able to significantly attenuate oxidative stress and improve mitochondrial function. Furthermore, edaravone was found to reduce apoptosis in Neuro2a cells through modulation of mitochondria-dependent apoptosis pathways. Interestingly, our result also demonstrated that edaravone was able to up-regulate VMAT2 expression in N2a cells in a dose-dependent manner. Our findings enhance the understanding of the neuro-protective effects of edaravone in cell models and suggest that edaravone offers significant protection in a PD-related in vitro model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  • Amemiya S, Kamiya T, Nito C, Inaba T, Kato K, Ueda M, Shimazaki K, Katayama Y (2005) Anti-apoptotic and neuroprotective effects of edaravone following transient focal ischemia in rats. Eur J Pharmacol 516:125–130

    Article  PubMed  CAS  Google Scholar 

  • Bonifati V, Rizzu P, van Baren MJ et al (2003a) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259

    Article  PubMed  CAS  Google Scholar 

  • Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N, van Swieten JC, Brice A, van Duijn CM, Oostra B, Meco G et al (2003b) DJ-1 (PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 24:159–160

    Article  PubMed  CAS  Google Scholar 

  • Canet-Avilés RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A 101:9103–9108

    Article  PubMed  Google Scholar 

  • Chen H, Wang S, Ding JH, Hu G (2008) Edaravone protects against MPP+-induced cytotoxicity in rat primary cultured astrocytes via inhibition of mitochondrial apoptotic pathway. J Neurochem 106(6):2345–2352

    Article  PubMed  CAS  Google Scholar 

  • Cookson MR (2012) Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harb Perspect Med 2(9):a009415

    Article  PubMed  Google Scholar 

  • Crosiers D, Theuns J, Cras P, Van Broeckhoven C (2011) Parkinson disease: insights in clinical, genetic and pathological features of monogenic disease subtypes. J Chem Neuroanat 42(2):131–141

    Article  PubMed  CAS  Google Scholar 

  • Deeg S, Gralle M, Sroka K, Bahr M, Wouters FS, Kermer P (2010a) BAG1 restores formation of functional DJ-1 L166P dimers and DJ-1 chaperone activity. J Cell Biol 188:505–513

    Article  PubMed  CAS  Google Scholar 

  • Deeg S, Gralle M, Sroka K, Bahr M, Wouters FS, Kermer P (2010b) BAG1 restores formation of functional DJ-1 L166P dimers and DJ-1 chaperone activity. J Cell Biol 188:505–513

    Article  PubMed  CAS  Google Scholar 

  • Dexter DT, Jenner P (2013) Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med [Epub ahead of print]

  • Edaravone Acute Infarction Study G (2003) Effect of a novel free radical scavenger, edaravone (mci-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 15:222–229

    Article  Google Scholar 

  • Fan J, Ren H, Jia N, Fei E, Zhou T, Jiang P, Wu M, Wang G (2008) DJ-1 decreases Bax expression through repressing p53 transcriptional activity. J Biol Chem 283:4022–4030

    Article  PubMed  CAS  Google Scholar 

  • Giaime E, Sunyach C, Druon C et al (2010) Loss of function of DJ-1 triggered by Parkinson’s disease-associated mutation is due to proteolytic resistance to caspase-6. Cell Death Differ 17:158–169

    Article  PubMed  CAS  Google Scholar 

  • Glatt CE, Wahner AD, White DJ, Ruiz-Linares A, Ritz B (2006) Gain-offunction haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women. Hum Mol Genet 15:299–305

    Article  PubMed  CAS  Google Scholar 

  • Goldberg MS, Pisani A, Haburcak M et al (2005) Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45:489–496

    Article  PubMed  CAS  Google Scholar 

  • Ito H, Wate R, Zhang J, Ohnishi S, Kaneko S et al (2008) Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol 213:448–455

    Article  PubMed  CAS  Google Scholar 

  • Itoh T, Satou T, Nishida S, Tsubaki M, Hashimoto S et al (2009) The novel free radical scavenger, edaravone, increases neural stem cell number around the area of damage following rat traumatic brain injury. Neurotox Res 16:378–389

    Article  PubMed  CAS  Google Scholar 

  • Kawai H, Nakai H, Suga M, Yuki S, Watanabe T, Saito KI (1997) Effects of a novel free radical scavenger, MCI-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model. J Pharmacol Exp Ther 281(2):921–927

    PubMed  CAS  Google Scholar 

  • Kawasaki T, Ishihara K, Ago Y, Nakamura S, Itoh S, Baba A, Matsuda T (2006) Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum. Eur J Pharmacol 542:92–99

    Article  PubMed  CAS  Google Scholar 

  • Kawasaki T, Ishihara K, Ago Y, Baba A, Matsuda T (2007) Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger, prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the substantia nigra but not the striatum. J Pharmacol Exp Ther 322(1):274–281

    Article  PubMed  CAS  Google Scholar 

  • Kim RH, Smith PD, Aleyasin H et al (2005) Hypersensitivity of DJ-1-deficient mice to 1-mthyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and oxidative stress. Proc Natl Acad Aci U S A 102:5215–5220

    Article  CAS  Google Scholar 

  • Lang AE, Lozano AM (1998) Parkinson's disease. First of two parts. N Engl J Med 339:1044–1053

    Article  PubMed  CAS  Google Scholar 

  • Lees AJ, Hardy J, Revesz T (2009) Parkinson's disease. Lancet 373:2055–2066

    Article  PubMed  CAS  Google Scholar 

  • Lin Z, Zhao Y, Chung CY, Zhou Y, Xiong N, et al. (2010) High regulatability favors genetic selection in SLC18A2, a vesicular monoamine transporter essential for life. FASEB J 24:2191–2200

    Google Scholar 

  • Meulener M, Whitworth AJ, Armstrong-Gold CE, Rizzu P, Heutink P, Wes PD, Pallanck LJ, Bonini NM (2005) Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson’s disease. Curr Biol 15:1572–1577

    Article  PubMed  CAS  Google Scholar 

  • Mo JS, Kim MY, Ann EJ, Hong JA, Park HS (2008) DJ-1 modulates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death. Cell Death Differ 15:1030–1041

    Article  PubMed  CAS  Google Scholar 

  • Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87

    Article  PubMed  CAS  Google Scholar 

  • Nakamura T, Kuroda Y, Yamashita S, Zhang X, Miyamoto O et al (2008) Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage. Stroke 39:463–469

    Article  PubMed  CAS  Google Scholar 

  • Okamura N, Villemagne VL, Drago J, Pejoska S, Dhamija RK et al (2010) In vivo measurement of vesicular monoamine transporter type 2 density in Parkinson disease with (18)F-AV-133. J Nucl Med 51:223–228

    Article  PubMed  Google Scholar 

  • Rajesh KG, Sasaguri S, Suzuki R, Maeda H (2003) Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression. Am J Physiol Heart Circ Physiol 285:H2171–H2178

    PubMed  CAS  Google Scholar 

  • Ren H, Fu K, Mu C, Zhen X, Wang G (2012) L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL. Mol Neurodegener 7:40

    Article  PubMed  CAS  Google Scholar 

  • Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P (2004) Vandenabeele toxic proteins released from mitochondria in cell death. Oncogene 23:2861–2874

    Article  PubMed  CAS  Google Scholar 

  • Sharma P, Sinha M, Shukla R, Garg RK, Verma R, Singh MK (2011) A randomized controlled clinical trial to compare the safety and efficacy of edaravone in acute ischemic stroke. Ann Indian Acad Neurol 14(2):103–106

    Article  PubMed  Google Scholar 

  • Sheng B, Gong K, Niu Y, Liu L, Yan Y, Lu G, Zhang L, Hu M, Zhao N, Zhang X, Tang P, Gong Y (2009) Inhibition of gamma-secretase activity reduces Abeta production, reduces oxidative stress, increases mitochondrial activity and leads to reduced vulnerability to apoptosis: implications for the treatment of Alzheimer's disease. Free Radic Biol Med 46(10):1362–1375

    Article  PubMed  CAS  Google Scholar 

  • Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X (2012) Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease. J Neurochem 120(3):419–429

    Article  PubMed  CAS  Google Scholar 

  • Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5:213–218

    Article  PubMed  CAS  Google Scholar 

  • Tsujita K, Shimomura H, Kawano H, Hokamaki J, Fukuda M, Yamashita T, Hida S, Nakamura Y, Nagayoshi Y, Sakamoto T, Yoshimura M, Arai H, Ogawa H (2004) Effects of edaravone on reperfusion injury in patients with acute myocardial infarction. Am J Cardiol 94:481–484

    Article  PubMed  CAS  Google Scholar 

  • Tsujita K, Shimomura H, Kaikita K, Kawano H, Hokamaki J, Nagayoshi Y, Yamashita T, Fukuda M, Nakamura Y, Sakamoto T, Yoshimura M, Ogawa H (2006) Long-term efficacy of edaravone in patients with acute myocardial infarction. Circ J 70:832–837

    Article  PubMed  CAS  Google Scholar 

  • Vila M, Jackson-Lewis V, Vukosavic S, Djaldetti R, Liberatore G, Offen D, Korsmeyer SJ, Przedborski S (2001) Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 98:2837–2842

    Article  PubMed  CAS  Google Scholar 

  • Xiong N, Xiong J, Khare G, Chen C, Huang J, Zhao Y, Zhang Z, Qiao X, Feng Y, Reesaul H, Zhang Y, Sun S, Lin Z, Wang T (2011a) Edaravone guards dopamine neurons in a rotenone model for Parkinson's disease. PLoS One 6(6):e20677

    Article  PubMed  CAS  Google Scholar 

  • Xiong N, Xiong J, Khare G, Chen C, Huang J, Zhao Y, Zhang Z, Qiao X, Feng Y, Reesaul H, Zhang Y, Sun S, Lin Z, Wang T (2011b) Edaravone guards dopamine neurons in a rotenone model for Parkinson’s disease. PLoS One 6(6):e20677

    Article  PubMed  CAS  Google Scholar 

  • Yan Y, Gong K, Ma T, Zhang L, Zhao N, Zhang X, Tang P, Gong Y (2012) Protective effect of edaravone against Alzheimer's disease-relevant insults in neuroblastoma N2a cells. Neurosci Lett 531(2):160–165

    Article  PubMed  CAS  Google Scholar 

  • Ying HS, Gottron FJ, Choi DW (2001) Assessment of cell viability in primary neuronal cultures. Curr Protoc Neurosci Chapter 7:Unit 7.18. doi:10.1002/0471142301.ns0718s13

  • Yuan WJ, Yasuhara T, Shingo T, Muraoka K, Agari T et al (2008a) Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons. BMC Neurosci 9:75

    Article  PubMed  Google Scholar 

  • Yuan WJ, Yasuhara T, Shingo T et al (2008b) Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons. BMC Neurosci 9:75

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhiying Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, B., Yu, D. & Xu, Z. Edaravone Prevents Neurotoxicity of Mutant L166P DJ-1 in Parkinson’s Disease. J Mol Neurosci 51, 539–549 (2013). https://doi.org/10.1007/s12031-013-0022-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-013-0022-8

Keywords

Navigation