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

Author(s)

Fernandes Ferreira, Ana Flavia ^[1] ; Singulani, Monique Patricio ^{[1, 2]} ; Ulrich, Henning ^[3] ; Feng, Zhong-Ping ^[4] ; Sun, Hong-Shuo ^{[4, 5]} ; Britto, Luiz Roberto ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Dept & Inst Psychiat, Lab Neurosci LIM27, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo - Brazil

^[4] Univ Toronto, Temerty Fac Med, Dept Physiol, Toronto, ON - Canada

^[5] Univ Toronto, Temerty Fac Med, Dept Surg, Toronto, ON - Canada

• Document type: Journal article
• Source: Molecular Neurobiology; JAN 2022.
• Web of Science Citations: 0

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-3 beta/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. (AU)

• FAPESP's process: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/02109-3 - Involvement of TRPM2 channel in neurodegeneration and microglial activation in a Parkinson's Disease model induced by 6-hydroxydopamine
• Grantee: Ana Flávia Fernandes Ferreira
• Support Opportunities: Scholarships in Brazil - Doctorate