| Full text | |
| Author(s): |
Ferreira, Ana Flavia F.
;
Ulrich, Henning
;
Feng, Zhong-Ping
;
Sun, Hong-Shuo
;
Britto, Luiz Roberto
Total Authors: 5
|
| Document type: | Journal article |
| Source: | Experimental Neurology; v. 377, p. 15-pg., 2024-04-25. |
| Abstract | |
Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuron death and neuroinflammation. Emerging evidence points to the involvement of the transient receptor potential melastatin 2 (TRPM2) channel in neuron death and glial activation in several neurodegenerative diseases. However, the involvement of TRPM2 in PD and specifically its relation to the neuroinflammation aspect of the disease remains poorly understood. Here, we hypothesized that AG490, a TRPM2 inhibitor, can be used as a treatment in a mouse model of PD. Mice underwent stereotaxic surgery for 6-hydroxydopamine (6-OHDA) administration in the right striatum. Motor behavioral tests (apomorphine, cylinder, and rotarod) were performed on day 3 post-injection to confirm the PD model induction. AG490 was then daily injected i.p. between days 3 to 6 after surgery. On day 6, motor behavior was assessed again. Substantia nigra (SNc) and striatum (CPu) were collected for immunohistochemistry, immunoblotting, and RT-qPCR analysis on day 7. Our results revealed that AG490 post-treatment reduced motor behavior impairment and nigrostriatal neurodegeneration. In addition, the compound prevented TRPM2 upregulation and changes of the Akt/GSK-38/caspase-3 signaling pathway. The TRPM2 inhibition also avoids the glial morphology changes observed in the PD group. Remarkably, the morphometrical analysis revealed that the ameboid-shaped microglia, found in 6-OHDA-injected animals, were no longer present in the AG490-treated group. These results indicate that AG490 treatment can reduce dopaminergic neuronal death and suppress neuroinflammation in a PD mouse model. Inhibition of TRPM2 by AG490 could then represent a potential therapeutical strategy to be evaluated for PD treatment. (AU) | |
| 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 |
| 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: | 22/14820-9 - Possible neuroprotection strategies in Parkinson's Disease |
| Grantee: | Luiz Roberto Giorgetti de Britto |
| Support Opportunities: | Regular Research Grants |