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.
Highlights
Nutraceuticals derived from spices such as turmeric, ginger, and garlic have been demonstrated to regulate central nervous system (CNS) disorders by modulating inflammatory pathways
Vanillin (1) was transformed to ketone 2 through three sequential steps, with the phenolic hydroxyl protected with t-butyldimethylsilyl group, by an aldol reaction with acetone, and olefin reduction by catalytic hydrogenation with palladium on charcoal
A robust increase in nitric oxide (NO) production and proinflammatory cytokines (i.e., IL-6 and tumor necrosis factor-α (TNF-α)) was markedly blocked by exposure to 6-paradol, indicating that it may function as a neuroprotectant that reduces inflammatory responses
Summary
Nutraceuticals derived from spices such as turmeric, ginger, and garlic have been demonstrated to regulate central nervous system (CNS) disorders by modulating inflammatory pathways. Epidemiological data reveals that populations in places like the Indian subcontinent, where people regularly consume spices, have a lower prevalence of neurodegenerative diseases compared with those of countries in the western world [1]. This includes spices such as turmeric, red pepper, black pepper, licorice, clove, ginger, garlic, coriander, and cinnamon. Many previous studies have reported that ginger oils exert potential effects against cancer, skin problems, gastrointestinal tract diseases, and CNS disorders associated with oxidative and inflammatory stresses [9]. 6-shogaol was revealed to be neuroprotective in the septic brain or transient global ischemia via the attenuation of microglial activation [12], a key component of neuroinflammation that is a feature in many CNS disorders [17,18]
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