Paradols are non-pungent and biotransformed metabolites of shogaols and reduce inflammatory responses as well as oxidative stress as shogaols. Recently,
shogaol has been noted to possess therapeutic potential against several central nervous system (CNS) disorders, including
cerebral ischemia, by reducing
neuroinflammation in microglia. Therefore, paradol could be used to improve
neuroinflammation-associated CNS disorders. Here, we synthesized paradol derivatives (2- to 10-paradols). Through the initial screening for anti-inflammatory activities using
lipopolysaccharide (LPS)-stimulated BV2 microglia,
6-paradol was chosen to be the most effective compound without cytotoxicity. Pretreatment with
6-paradol reduced neuroinflammatory responses in LPS-stimulated BV2 microglia by a concentration-dependent manner, which includes reduced NO production by inhibiting iNOS upregulation and lowered secretion of proinflammatory
cytokines (IL-6 and TNF-α). To pursue whether the beneficial in vitro effects of
6-paradol leads towards in vivo
therapeutic effects on transient focal
cerebral ischemia characterized by
neuroinflammation, we employed
middle cerebral artery occlusion (MCAO)/reperfusion (M/R). Administration of
6-paradol immediately after reperfusion significantly reduced brain damage in M/R-challenged mice as assessed by
brain infarction, neurological deficit, and neural cell survival and death. Furthermore, as observed in cultured microglia,
6-paradol administration markedly reduced
neuroinflammation in M/R-challenged brains by attenuating microglial activation and reducing the number of cells expressing iNOS and TNF-α, both of which are known to be produced in microglia following M/R challenge. Collectively, this study provides evidences that
6-paradol effectively protects brain after
cerebral ischemia, likely by attenuating
neuroinflammation in microglia, suggesting it as a potential therapeutic agent to treat
cerebral ischemia.