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Inhibition of TRPM2 by AG490 Is Neuroprotective in a Parkinson’s Disease Animal Model

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Abstract

Parkinson’s disease (PD) is characterized by motor impairment and dopaminergic neuronal loss. There is no cure for the disease, and treatments have several limitations. The transient receptor potential melastatin 2 (TRPM2), a calcium-permeable non-selective cation channel, has been reported to be upregulated in neuronal death. However, there are no in vivo studies evaluating TRPM2’s role and neuroprotective effects in PD. Here, we test the hypothesis that TRPM2 is upregulated in the 6-hydroxydopamine (6-OHDA) mouse model of PD and that its inhibition, by the AG490, is neuroprotective. For that, AG490 or vehicle were intraperitoneally administered into C57BL/6 mice. Mice then received 6-OHDA into the right striatum. Motor behavior assessments were evaluated 6, 13, and 20 days after surgery using the cylinder and apomorphine-induced rotational testes, and 7, 14, and 21 days after surgery using rotarod test. Brain samples of substantia nigra (SNc) and striatum (CPu) were collected for immunohistochemistry and immunoblotting on days 7 and 21. We showed that TRPM2 protein expression was upregulated in 6-OHDA-treated animals. In addition, AG490 prevented dopaminergic neuron loss, microglial activation, and astrocyte reactivity in 6-OHDA-treated animals. The compound improved motor behaviors and Akt/GSK-3β/caspase-3 signaling. We conclude that TRPM2 inhibition by AG490 is neuroprotective in the 6-OHDA model and that the TRPM2 channel may represent a potential therapeutic target for PD.

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The data generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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References

  1. Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA (2012) Parkinson’s disease. Subcell Biochem 65:389–455. https://doi.org/10.1007/978-94-007-5416-4_16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tysnes O-B, Storstein A (2017) Epidemiology of Parkinson’s disease. J Neural Transm 124:901–905. https://doi.org/10.1007/s00702-017-1686-y

    Article  PubMed  Google Scholar 

  3. Dorsey ER, Sherer T, Okun MS, Bloem BR (2018) The emerging evidence of the Parkinson pandemic. J Parkinsons Dis 8:S3–S8. https://doi.org/10.3233/JPD-181474

    Article  PubMed  PubMed Central  Google Scholar 

  4. Feigin VL et al (2017) Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol 16:877–897. https://doi.org/10.1016/S1474-4422(17)30299-5

    Article  Google Scholar 

  5. (2019) Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18:459–480.https://doi.org/10.1016/s1474-4422(18)30499-x

  6. Aquino CC, Fox SH (2015) Clinical spectrum of levodopa-induced complications. Mov Disord 30:80–89. https://doi.org/10.1002/mds.26125

    Article  CAS  PubMed  Google Scholar 

  7. Salamon A, Zádori D, Szpisjak L, Klivényi P, Vécsei L (2020) Neuroprotection in Parkinson’s disease: facts and hopes. J Neural Transm 127:821–829. https://doi.org/10.1007/s00702-019-02115-8

    Article  PubMed  Google Scholar 

  8. Torti M, Bravi D, Vacca L, Stocchi F (2019) Are all dopamine agonists essentially the same? Drugs 79:693–703. https://doi.org/10.1007/s40265-019-01103-2

    Article  CAS  PubMed  Google Scholar 

  9. Cankaya S, Cankaya B, Kilic U, Kilic E, Yulug B (2019) The therapeutic role of minocycline in Parkinson’s disease. Drugs Context 8:212553. https://doi.org/10.7573/dic.212553

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kirik D, Georgievska B, Björklund A (2004) Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat Neurosci 7:105–110. https://doi.org/10.1038/nn1175

    Article  CAS  PubMed  Google Scholar 

  11. Park HW et al (2020) Intrastriatal administration of coenzyme Q10 enhances neuroprotection in a Parkinson’s disease rat model. Sci Rep 10:9572. https://doi.org/10.1038/s41598-020-66493-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hou L et al (2019) Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse Parkinson’s disease model. Redox Biol 22:101134. https://doi.org/10.1016/j.redox.2019.101134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Whone AL et al (2019) Extended treatment with glial cell line-derived neurotrophic factor in Parkinson’s disease. J Parkinsons Dis 9:301–313. https://doi.org/10.3233/jpd-191576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee TK, Yankee EL (2021) A review on Parkinson’s disease treatment. Neuroimmunol Neuroinflamm 8, [Online First]. https://doi.org/10.20517/2347-8659.2020.58

  15. Fonfria E et al (2006) TRPM2 is elevated in the tMCAO stroke model, transcriptionally regulated, and functionally expressed in C13 microglia. J Recept Signal Transduct Res 26:179–198. https://doi.org/10.1080/10799890600637522

    Article  CAS  PubMed  Google Scholar 

  16. Ostapchenko VG et al (2015) The transient receptor potential melastatin 2 (TRPM2) channel contributes to β-amyloid oligomer-related neurotoxicity and memory impairment. J Neurosci 35:15157–15169. https://doi.org/10.1523/jneurosci.4081-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jang Y et al (2015) TRPM2, a susceptibility gene for bipolar disorder, regulates glycogen synthase kinase-3 activity in the brain. J Neurosci 35:11811. https://doi.org/10.1523/JNEUROSCI.5251-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Takada Y, Numata T, Mori Y (2013) Targeting TRPs in neurodegenerative disorders. Curr Top Med Chem 13:322–334. https://doi.org/10.2174/1568026611313030009

    Article  CAS  PubMed  Google Scholar 

  19. Dati LM et al (2017) Carvacrol promotes neuroprotection in the mouse hemiparkinsonian model. Neuroscience 356:176–181. https://doi.org/10.1016/j.neuroscience.2017.05.013

    Article  CAS  PubMed  Google Scholar 

  20. Fonfria E et al (2006) Tissue distribution profiles of the human TRPM cation channel family. J Recept Signal Transduct Res 26:159–178. https://doi.org/10.1080/10799890600637506

    Article  CAS  PubMed  Google Scholar 

  21. Belrose JC, Jackson MF (2018) TRPM2: a candidate therapeutic target for treating neurological diseases. Acta Pharmacol Sin 39:722–732. https://doi.org/10.1038/aps.2018.31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yamamoto S et al (2008) TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med 14:738–747. https://doi.org/10.1038/nm1758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. An X et al (2019) Increasing the TRPM2 channel expression in human neuroblastoma SH-SY5Y cells augments the susceptibility to ROS-induced cell death. Cells 8. https://doi.org/10.3390/cells8010028

  24. Takahashi N, Kozai D, Kobayashi R, Ebert M, Mori Y (2011) Roles of TRPM2 in oxidative stress. Cell Calcium 50:279–287. https://doi.org/10.1016/j.ceca.2011.04.006

    Article  CAS  PubMed  Google Scholar 

  25. Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 3:461–491. https://doi.org/10.3233/jpd-130230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Naziroğlu M, Lückhoff A, Jüngling E (2007) Antagonist effect of flufenamic acid on TRPM2 cation channels activated by hydrogen peroxide. Cell Biochem Funct 25:383–387. https://doi.org/10.1002/cbf.1310

    Article  PubMed  Google Scholar 

  27. Hill K, McNulty S, Randall AD (2004) Inhibition of TRPM2 channels by the antifungal agents clotrimazole and econazole. Naunyn-Schmiedeberg’s Arch Pharmacol 370:227–237. https://doi.org/10.1007/s00210-004-0981-y

    Article  CAS  Google Scholar 

  28. Kraft R, Grimm C, Frenzel H, Harteneck C (2006) Inhibition of TRPM2 cation channels by N-(p-amylcinnamoyl)anthranilic acid. Br J Pharmacol 148:264–273. https://doi.org/10.1038/sj.bjp.0706739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shimizu S et al (2014) Inhibitory effects of AG490 on H2O2-induced TRPM2-mediated Ca(2+) entry. Eur J Pharmacol 742:22–30. https://doi.org/10.1016/j.ejphar.2014.08.023

    Article  CAS  PubMed  Google Scholar 

  30. Li F et al (2019) Neuroprotective effects of AG490 in neonatal hypoxic-ischemic brain injury. Mol Neurobiol 56:8109–8123. https://doi.org/10.1007/s12035-019-01656-z

    Article  CAS  PubMed  Google Scholar 

  31. Stott SR, Barker RA (2014) Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of Parkinson’s disease. Eur J Neurosci 39:1042–1056. https://doi.org/10.1111/ejn.12459

    Article  PubMed  Google Scholar 

  32. Garcia PC, Real CC, Britto LR (2017) The impact of short and long-term exercise on the expression of Arc and AMPARs during evolution of the 6-hydroxy-dopamine animal model of Parkinson’s disease. J Mol Neurosci 61:542–552. https://doi.org/10.1007/s12031-017-0896-y

    Article  CAS  PubMed  Google Scholar 

  33. Ferreira AFF et al (2020) Physical exercise protects against mitochondria alterations in the 6-hidroxydopamine rat model of Parkinson’s disease. Behav Brain Res 387:112607. https://doi.org/10.1016/j.bbr.2020.112607

    Article  CAS  PubMed  Google Scholar 

  34. Hernandes MS, Café-Mendes CC, Britto LR (2013) NADPH oxidase and the degeneration of dopaminergic neurons in parkinsonian mice. Oxid Med Cell Longev 2013:157857. https://doi.org/10.1155/2013/157857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Binda KH et al (2021) Exercise protects synaptic density in a rat model of Parkinson’s disease. Exp Neurol 342:113741. https://doi.org/10.1016/j.expneurol.2021.113741

    Article  CAS  PubMed  Google Scholar 

  36. Paxinos G, Franklin KB (2019) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates. Academic Press

  37. Cho C et al (2019) Evaluating analgesic efficacy and administration route following craniotomy in mice using the grimace scale. Sci Rep 9:359. https://doi.org/10.1038/s41598-018-36897-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Binda KH, Real CC, Ferreira AFF, Britto LR, Chacur M (2020) Antinociceptive effects of treadmill exercise in a rat model of Parkinson’s disease: the role of cannabinoid and opioid receptors. Brain Res 1727:146521. https://doi.org/10.1016/j.brainres.2019.146521

    Article  CAS  PubMed  Google Scholar 

  39. Kotra LP, Park J (2017) In: S Chackalamannil, D Rotella, SE Ward (eds) Comprehensive Medicinal Chemistry III. Elsevier, pp 439–473

  40. Singulani MP et al (2020) Impairment of PGC-1α-mediated mitochondrial biogenesis precedes mitochondrial dysfunction and Alzheimer’s pathology in the 3xTg mouse model of Alzheimer’s disease. Exp Gerontol 133:110882. https://doi.org/10.1016/j.exger.2020.110882

    Article  CAS  PubMed  Google Scholar 

  41. Iancu R, Mohapel P, Brundin P, Paul G (2005) Behavioral characterization of a unilateral 6-OHDA-lesion model of Parkinson’s disease in mice. Behav Brain Res 162:1–10. https://doi.org/10.1016/j.bbr.2005.02.023

    Article  CAS  PubMed  Google Scholar 

  42. Real CC, Garcia PC, Britto LRG (2017) Treadmill exercise prevents increase of neuroinflammation markers involved in the dopaminergic damage of the 6-OHDA Parkinson’s disease model. J Mol Neurosci 63:36–49. https://doi.org/10.1007/s12031-017-0955-4

    Article  CAS  PubMed  Google Scholar 

  43. Hendrickx DAE, van Eden CG, Schuurman KG, Hamann J, Huitinga I (2017) Staining of HLA-DR, Iba1 and CD68 in human microglia reveals partially overlapping expression depending on cellular morphology and pathology. J Neuroimmunol 309:12–22. https://doi.org/10.1016/j.jneuroim.2017.04.007

    Article  CAS  PubMed  Google Scholar 

  44. Jurga AM, Paleczna M, Kuter KZ (2020) Overview of general and discriminating markers of differential microglia phenotypes. Front Cell Neurosci 14:198. https://doi.org/10.3389/fncel.2020.00198

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zhu Y-F et al (2020) Characteristic response of striatal astrocytes to dopamine depletion. Neural Regen Res 15:724–730. https://doi.org/10.4103/1673-5374.266917

    Article  PubMed  Google Scholar 

  46. Maurer U, Preiss F, Brauns-Schubert P, Schlicher L, Charvet C (2014) GSK-3 - at the crossroads of cell death and survival. J Cell Sci 127:1369–1378. https://doi.org/10.1242/jcs.138057

    Article  CAS  PubMed  Google Scholar 

  47. Marchetti B (2018) Wnt/β-catenin signaling pathway governs a full program for dopaminergic neuron survival, neurorescue and regeneration in the MPTP mouse model of Parkinson’s disease. Int J Mol Sci 19. https://doi.org/10.3390/ijms19123743

  48. Huang S et al (2017) Transient receptor potential melastatin 2 channels (TRPM2) mediate neonatal hypoxic-ischemic brain injury in mice. Exp Neurol 296:32–40. https://doi.org/10.1016/j.expneurol.2017.06.023

    Article  CAS  PubMed  Google Scholar 

  49. Jeon BS, Jackson-Lewis V, Burke RE (1995) 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 4:131–137. https://doi.org/10.1006/neur.1995.0016

    Article  CAS  PubMed  Google Scholar 

  50. Zuch CL et al (2000) Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. J Comp Neurol 427:440–454. https://doi.org/10.1002/1096-9861(20001120)427:3%3c440::aid-cne10%3e3.0.co;2-7

    Article  CAS  PubMed  Google Scholar 

  51. Alim I, Teves L, Li R, Mori Y, Tymianski M (2013) Modulation of NMDAR subunit expression by TRPM2 channels regulates neuronal vulnerability to ischemic cell death. J Neurosci 33:17264–17277. https://doi.org/10.1523/jneurosci.1729-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kwon HS, Koh S-H (2020) Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 9:42. https://doi.org/10.1186/s40035-020-00221-2

    Article  PubMed  PubMed Central  Google Scholar 

  53. Kraft R et al (2004) Hydrogen peroxide and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia. Am J Physiol Cell Physiol 286:C129-137. https://doi.org/10.1152/ajpcell.00331.2003

    Article  CAS  PubMed  Google Scholar 

  54. Lee M et al (2010) Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. FASEB J 24:2533–2545. https://doi.org/10.1096/fj.09-149997

    Article  CAS  PubMed  Google Scholar 

  55. Alawieyah Syed Mortadza S, Sim JA, Neubrand VE, Jiang LH (2018) A critical role of TRPM2 channel in Aβ(42) -induced microglial activation and generation of tumor necrosis factor-α. Glia 66:562–575. https://doi.org/10.1002/glia.23265

    Article  PubMed  Google Scholar 

  56. Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354–365. https://doi.org/10.1016/j.nurt.2010.05.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hernandez-Baltazar D, Mendoza-Garrido ME, Martinez-Fong D (2013) Activation of GSK-3β and caspase-3 occurs in nigral dopamine neurons during the development of apoptosis activated by a striatal injection of 6-hydroxydopamine. PLoS ONE 8:e70951. https://doi.org/10.1371/journal.pone.0070951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Malagelada C, Jin ZH, Greene LA (2008) RTP801 is induced in Parkinson’s disease and mediates neuron death by inhibiting Akt phosphorylation/activation. J Neurosci 28:14363–14371. https://doi.org/10.1523/jneurosci.3928-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kozikowski AP et al (2006) Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson’s disease. ChemMedChem 1:256–266. https://doi.org/10.1002/cmdc.200500039

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Adilson S. Alves for his technical assistance.

Funding

This study was funded by Coordination for the Improvement of Higher Education Personnel (CAPES, Brazil—Finance Code 001), the São Paulo Research Foundation (FAPESP, Brazil, project # 2018/07366–4), and the National Council for Scientific and Technological Development (CNPq, Brazil, project #303006/2018–8). AFFF received a PhD fellowship from FAPESP under Grant Agreement No 2020/02109–3.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    Ana Flávia Fernandes Ferreira, Monique Patricio Singulani & Luiz Roberto Britto

  2. Laboratory of Neurosciences - LIM27, Department & Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil

    Monique Patricio Singulani

  3. Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil

    Henning Ulrich

  4. Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada

    Zhong-Ping Feng & Hong-Shuo Sun

  5. Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada

    Hong-Shuo Sun

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  1. Ana Flávia Fernandes Ferreira
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Contributions

Ana Flávia Fernandes Ferreira: conceptualization, investigation, methodology, validation, data curation, formal analysis, project administration, writing—original draft preparation, writing—review and editing. Monique Patricio Singulani: investigation, methodology, writing—review and editing. Henning Ulrich: funding acquisition, writing—review and editing. Zhong-Ping Feng: conceptualization, writing—review and editing. Hong-Shuo Sun: conceptualization, writing—review and editing. Luiz Roberto Britto: conceptualization, project administration, funding acquisition, supervision, writing—review and editing. All authors read, reviewed, and approved the final version of the manuscript.

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Correspondence to Ana Flávia Fernandes Ferreira.

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This study was performed in line with ARRIVE guidelines, the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978), and the National Council for the control of Animal Experimentation (CONCEA, Brazil) guidelines. Approval was granted by the Ethics Committee for Animal Research of the Institute of Biomedical Sciences of the University of São Paulo (CEUA-ICB/USP, Brazil, protocol number: 8395080450).

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Ferreira, A.F.F., Singulani, M.P., Ulrich, H. et al. Inhibition of TRPM2 by AG490 Is Neuroprotective in a Parkinson’s Disease Animal Model. Mol Neurobiol 59, 1543–1559 (2022). https://doi.org/10.1007/s12035-022-02723-8

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