Hesperidin, nobiletin, and tangeretin are collectively responsible for the anti-neuroinflammatory capacity of tangerine peel (Citri reticulatae pericarpium).

Inhibiting microglial activation-mediated neuroinflammation has become a convincing target for the development of functional foods to treat neurodegenerative diseases. Tangerine peel (Citri reticulatae pericarpium) has potent anti-inflammatory capacity; however, its anti-neuroinflammatory capacity and the corresponding active compounds remain unclear. To this end, the composition of a tangerine peel ethanolic extract was analysed by LC-MS, and the anti-neuroinflammatory ability was evaluated using a lipopolysaccharide (LPS)-activated BV2 microglia culture system. Hesperidin is the most predominant flavonoid in tangerine peel, followed by tangeretin and nobiletin. Among the eight tested flavanone glycosides and polymethoxy flavones, only nobiletin displayed a capacity of>50% to inhibit LPS-induced proinflammatory NO, TNF-α, IL-1β and IL-6 secretion at a concentration of 100 μM. At 2 mg/ml, tangerine peel extract attenuated LPS-induced NO, TNF-α, IL-1β and IL-6 secretion by 90.6%, 80.2%, 66.7%, and 86.8%, respectively. Hesperidin, nobiletin, and tangeretin individually (at concentrations of 135, 40, and 60 μM, respectively) in 2 mg/ml tangerine peel extract were only mildly inhibitory, whereas in combination, they significantly inhibited LPS-induced proinflammatory cytokine expression at levels equal to that of 2 mg/ml tangerine peel extract. Overall, tangerine peel possesses potent anti-neuroinflammatory capacity, which is attributed to the collective effect of hesperidin, nobiletin, and tangeretin.