title: Neuroprotective effect of 6-paradol in focal cerebral ischemia involves the attenuation of neuroinflammatory responses in activated microglia.
abstract: 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.
authors: Laboratory of Pharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
authors: Bhakta Prasad
authors: BP
authors: Gaire
authors: Laboratory of Pharmacognosy, College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors: Oh Wook
authors: OW
authors: Kwon
authors: Laboratory of Medicinal Chemistry, College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors: Sung Hyuk
authors: SH
authors: Park
authors: Laboratory of Biochemistry, College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors: Kwang-Hoon
authors: KH
authors: Chun
authors: Laboratory of Pharmacognosy, College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors: Sun Yeou
authors: SY
authors: Kim
authors: Laboratory of Medicinal Chemistry, College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors: Dong Yun
authors: DY
authors: Shin
authors: Laboratory of Pharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
authors: Ji Woong
authors: JW
authors: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D007659:Ketones; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D006139:Guaiacol; C421614:6-paradol; D052247:Nitric Oxide Synthase Type II