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

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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Availability of Data and Material

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

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Not applicable.

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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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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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  • DOI: https://doi.org/10.1007/s12035-022-02723-8

Keywords

  • Transient receptor potential melastatin 2
  • AG490
  • Parkinson’s disease
  • 6-OHDA
  • Neuroprotection