Parkinson’s disease (PD) represents the second most common neurodegenerative disorder worldwide. So far, available treat- ments possess mere symptomatic action and severe long-term side effects, so the development of neuroprotective strategies is highly needed. It is now widely recognized that neuroinflammation is crucial in PD, especially in the disease progression. Therefore, pharmacological treatments able to modulate the pathological immune response may reveal effective in slowing disease progression. The microglial cells are the key component of the brain immune system and can be activated by adenosine through the interaction with A2AARs (A2A adenosine receptors). Indeed, the modulation of purinergic receptors has been associated with a slower degeneration of nigrostriatal dopaminergic cells in PD. Since previous findings demonstrating the ability of A2AAR antagonist 8-ethoxy-9-ethyladenine (ANR94) to protect nigrostriatal neurons from neuroinflammation in an animal model of PD (1), several ad hoc-designed A2AAR antagonists (ANR94 ana- logues) have been synthetized and tested in activated BV-2 microglial cells. To mimic neuroinflammation BV-2 cells were exposed to 100 ng/mL LPS or 0.5 mM MPP+ for 24 h. The potential anti-inflammatory activity of ANR94 analogues were evaluated by MTT assay and measuring the reactive oxygen spe- cies (ROS) levels by DCF-DA probe, while gene expression anal- yses of inflammatory cytokines such as TNFa, IL-1b and the pro-inflammatory enzymes iNOS and COX-2 were performed by RT-PCR. Interestingly, the newly synthetized compounds were more effective than the lead compound ANR94 in counteracting inflammatory damage suggesting their potential use as therapeu- tic agent to prevent/counteract PD. Of course, animal and clini- cal studies are needed to investigate their in vivo activity. This work was supported by MIUR-PRIN n. 20152HKF3Z and University of Camerino n. FPI000065. 1. Pinna A et al. (2005) Eur J Pharmacol 512, 157–164.
Barbalace MC, Freschi Michela, Scocco V, Lambertucci C, Hrelia S, Angeloni Cristina (2021). Newly synthetized A2AAR antagonists as anti-inflammatory strategy in Parkinson's disease. 111 RIVER ST, HOBOKEN 07030-5774, NJ USA : WILEY.
Newly synthetized A2AAR antagonists as anti-inflammatory strategy in Parkinson's disease
Barbalace MC;Freschi Michela;Hrelia S;Angeloni Cristina
2021
Abstract
Parkinson’s disease (PD) represents the second most common neurodegenerative disorder worldwide. So far, available treat- ments possess mere symptomatic action and severe long-term side effects, so the development of neuroprotective strategies is highly needed. It is now widely recognized that neuroinflammation is crucial in PD, especially in the disease progression. Therefore, pharmacological treatments able to modulate the pathological immune response may reveal effective in slowing disease progression. The microglial cells are the key component of the brain immune system and can be activated by adenosine through the interaction with A2AARs (A2A adenosine receptors). Indeed, the modulation of purinergic receptors has been associated with a slower degeneration of nigrostriatal dopaminergic cells in PD. Since previous findings demonstrating the ability of A2AAR antagonist 8-ethoxy-9-ethyladenine (ANR94) to protect nigrostriatal neurons from neuroinflammation in an animal model of PD (1), several ad hoc-designed A2AAR antagonists (ANR94 ana- logues) have been synthetized and tested in activated BV-2 microglial cells. To mimic neuroinflammation BV-2 cells were exposed to 100 ng/mL LPS or 0.5 mM MPP+ for 24 h. The potential anti-inflammatory activity of ANR94 analogues were evaluated by MTT assay and measuring the reactive oxygen spe- cies (ROS) levels by DCF-DA probe, while gene expression anal- yses of inflammatory cytokines such as TNFa, IL-1b and the pro-inflammatory enzymes iNOS and COX-2 were performed by RT-PCR. Interestingly, the newly synthetized compounds were more effective than the lead compound ANR94 in counteracting inflammatory damage suggesting their potential use as therapeu- tic agent to prevent/counteract PD. Of course, animal and clini- cal studies are needed to investigate their in vivo activity. This work was supported by MIUR-PRIN n. 20152HKF3Z and University of Camerino n. FPI000065. 1. Pinna A et al. (2005) Eur J Pharmacol 512, 157–164.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
