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Effect of Adenosine Receptor Antagonists on Adenosine-Pretreated PC12 Cells Exposed to Paraquat
Liangcheng Shang1, Yaobiao Huang1, Xin Xie1
1Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, Engineering Training Centre, China Jiliang University, Hangzhou, China.
Abstract:
Previous studies evaluated the adenosine receptor antagonists alone to determine their effects on oxidative stress, but little is known about adenosine's protective efficacy when oxidative injury occurs in vivo. Adenosine is a crucial signaling molecule recognized by four distinct G-protein-coupled receptors (GPCRs) (i.e., A1R, A2AR, A2BR, and A3R) and protects cells against pathological conditions. The present study was performed to evaluate the role of antagonist modulation in the setting of paraquat toxicity with adenosine pretreatment. First, PC12 cells were exposed to paraquat (850 μM) and adenosine (30 μM) to develop an in vitro model for the antagonist effect assay. Second, we found that the A1R antagonist DPCPX enhanced the viability of paraquat-induced PC12 cells that underwent adenosine pretreatment. Moreover, the A2AR antagonist ZM241385 decreased the viability of paraquat-induced PC12 cells that underwent adenosine pretreatment. Our findings indicate that adenosine protection requires a dual blockade of A1R and activation of A2AR to work at its full potential, and the A2B and A3 adenosine receptor antagonists increased paraquat-induced oxidative damage. This represents a novel pharmacological strategy based on A1/A2A interactions and can assist in clarifying the role played by AR antagonists in the treatment of neurodegenerative diseases.
Insights
Adenosine pretreatment protects against paraquat-induced oxidative stress, but requires blocking A1 receptors and activating A2A receptors for maximum efficacy. This finding offers a new strategy for neurodegenerative disease treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Adenosine is a key signaling molecule with protective effects against cellular damage.
- Adenosine exerts its functions through four G-protein-coupled receptors (A1R, A2AR, A2BR, A3R).
- The role of adenosine receptor antagonists in protecting against in vivo oxidative injury is not fully understood.
Purpose of the Study:
- To investigate the protective role of adenosine pretreatment against paraquat-induced oxidative stress.
- To evaluate the effects of specific adenosine receptor antagonists on paraquat toxicity.
- To elucidate the interaction between adenosine receptors in mediating protection against oxidative damage.
Main Methods:
- An in vitro model using PC12 cells exposed to paraquat and adenosine was developed.
- The effects of A1R antagonist DPCPX and A2AR antagonist ZM241385 on cell viability were assessed.
- The impact of A2B and A3 adenosine receptor antagonists on paraquat-induced oxidative damage was examined.
Main Results:
- A1R antagonist DPCPX enhanced PC12 cell viability after paraquat exposure and adenosine pretreatment.
- A2AR antagonist ZM241385 decreased PC12 cell viability under the same conditions.
- A2B and A3 adenosine receptor antagonists exacerbated paraquat-induced oxidative damage.
Conclusions:
- Adenosine's protective effect against oxidative stress is dependent on a dual blockade of A1R and activation of A2AR.
- This study proposes a novel pharmacological strategy targeting A1/A2A receptor interactions.
- Findings may aid in understanding the role of adenosine receptor antagonists in treating neurodegenerative diseases.
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