Auraptene in the Peels of Citrus kawachiensis (Kawachi Bankan) Ameliorates Lipopolysaccharide‐Induced Inflammation in the Mouse Brain

Abstract

Examination of the dried peel powder of Citrus kawachiensis, one of the citrus products of Ehime, Japan, showed that it contained naringin (NGIN; 44.02 ± 0.491 mg/g), narirutin (NRTN; 4.46 ± 0.0563 mg/g), auraptene (AUR; 4.07 ± 0.033 mg/g), and 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF; 0.27 ± 0.0039 mg/g). When this dried peel powder was orally preadministered at the dose of 1.2 or 2.4 g/kg/day for 7 days into lipopolysaccharide- (LPS-) injected mice, an animal model of systemic inflammation, it suppressed (1) LPS-induced loss of body weight and abnormal behavior in the open field, (2) LPS-induced activation of microglia and astrocytes in the hippocampus, and (3) LPS-induced expression of cyclooxygenase (COX)-2, which were coexpressed in astrocytes of these mice. When NGIN or AUR was preadministered to LPS-injected mice at an amount similar to that in the peel powder, AUR, but not NGIN, had the ability to suppress the LPS-induced inflammation in the brain of these model mice. The dried powder of flavedo tissue (the outer colored layer of the mesocarp of a citrus fruit) and juice, which contained sufficient amounts of AUR, also had anti-inflammatory effect. These results suggest that AUR was the main ingredient responsible for the anti-inflammatory property of the dried peels of C. kawachiensis.

Auraptene Acts as an Anti-Inflammatory Agent in the Mouse Brain

“…In our previous studies [8,9], we did not obtain any information to demonstrate that AUR penetrates the brain. Therefore, the final objective of the present study was to establish whether (1) AUR passes through the blood-brain barrier (BBB) and directly exerts anti-inflammatory effects in the brain; or (2) AUR remains in peripheral tissues and indirectly exerts anti-inflammatory effects in the brain.…”

“…We previously demonstrated that COX-2 was expressed in astrocytes in ischemic brains [8] and brains with LPS-induced inflammation [9]. Thus, the second objective of the present study was to determine whether AUR had any anti-inflammatory effects in cultured astrocytes.…”

“…Therefore, the effects of AUR in peripheral macrophages have attracted the attention of researchers [5][6][7]. We recently reported that AUR exerts anti-inflammatory effects not only in peripheral tissues, but also in the brain because it (1) suppresses inflammatory responses in the ischemic brain [8] and (2) ameliorates lipopolysaccharide (LPS)-induced inflammation in the mouse brain [9].…”

<i>Citrus</i> Flavonoids and Human Cancers

“…These AADs are essential for activating neutrophils and thus stimulate the formation of ROS in inflammatory tissues [51,52]. Citrus flavonoids were found to affect the activation of a number of cells involved in the immune response, including T and B lymphocytes [58]. It was reported that oral administration of Citrus flavonoids can alleviate alcoholic liver disease (ALD) through preventing excessive lipid formation, suppressing induction of inflammation in hepatocytes [53].…”

“…Moreover, tangeretin was reported to have markedly reduced LPS-stimulated phosphorylation of IκB-α and IKK-β, as well as the nuclear translocation of the p65 subunit of proinflammatory transcription factor NF-κβ [57]. Furthermore, auraptene (AUR) was reported to suppress the LPS-induced inflammation in the brain of model mice possibly through inhibiting the expression of (COX)-2 [58]. Naringenin was reported to have ameliorative effects on hyperglycemia-mediated inflammation in streptozocin (STZ) -nicotinamide induced DM in Wistar rats by decreasing the values of hematological, mRNA transcript and protein indices of inflammation [59].…”