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

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 up...

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Published in:Molecular neurobiology 2022-03, Vol.59 (3), p.1543-1559
Main Authors: Ferreira, Ana Flávia Fernandes, Singulani, Monique Patricio, Ulrich, Henning, Feng, Zhong-Ping, Sun, Hong-Shuo, Britto, Luiz Roberto
Format: Article
Language:English
Subjects:
6-Hydroxydopamine
AKT protein
Animal models
Animals
Apomorphine
Biomedical and Life Sciences
Biomedicine
Calcium permeability
Caspase-3
Cell Biology
Disease Models, Animal
Dopamine receptors
Dopaminergic Neurons - metabolism
Glycogen Synthase Kinase 3 beta - metabolism
Immunoblotting
Immunohistochemistry
Mice
Mice, Inbred C57BL
Movement disorders
Neostriatum
Neurobiology
Neurodegenerative diseases
Neurology
Neuroprotection
Neuroprotective Agents - metabolism
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
Neurosciences
Oxidopamine - pharmacology
Parkinson Disease - drug therapy
Parkinson Disease - metabolism
Parkinson's disease
Substantia nigra
Substantia Nigra - metabolism
Surgery
Therapeutic targets
Transient receptor potential proteins
TRPM Cation Channels - metabolism
Tyrphostins
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Summary: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.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-022-02723-8