Capsazepine Inhibits Astrocyte Activation and Attenuates Neuroinflammation by Targeting Syntaxin 7

Astrocytic neuroinflammation contributes as a key player in neurodegenerative diseases. Capsazepine is a frequently used transient receptor potential vanilloid 1 (TRPV1) inhibitor; however, its effects, as well as the target, on inflammation remain controversial. This study examines the anti-inflammatory actions of capsazepine and explores mechanisms beyond TRPV1 inhibition. By assessing astrocytic inflammation in vitro and in vivo experiments, capsazepine was found to inhibit astrocyte activation and attenuate neuroinflammation, with reduced levels of interleukin-6 and complement 3. When utilizing TRPV1 deficient models, no significant decrease was observed in the anti-inflammatory effects of capsazepine, suggesting there could be alternative targets in addition to TRPV1. Further investigations used drug affinity responsive target stability analysis, siRNA knockdown, cellular thermal shift assay, and molecular docking to hunt for new targets. Syntaxin 7, a modulator in cytokine trafficking and phagosome maturation, was identified as a crucial target to interact with capsazepine in the inhibition of astrocytic inflammation. This study verifies the anti-inflammatory effects of capsazepine and identifies Syntaxin 7 as a potential novel therapeutic target for treating neuroinflammation.