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.

The present study evaluated the effects of treatment with the citrus flavonoid, 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) on protection against memory impairment and neuronal death in a global cerebral ischemia mouse model. The results showed that HMF, administrated for three days immediately after ischemic surgery, protected against ischemia-induced memory dysfunction, rescued neuronal cell death in the CA1 cell layer, increased the production of BDNF, stimulated the autophosphorylation of CaMK II and suppressed microglial activation in the hippocampus. These results suggest that HMF has a neuroprotective effect after brain ischemia by inducing BDNF production and anti-inflammatory effects.

In patients with Parkinson’s disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that (1) auraptene (AUR), a natural prenyloxycoumain, suppressed inflammatory responses including the hyperactivation of microglia in the ischemic brain and inflamed brain, thereby inhibiting neuronal cell death; (2) 7-isopentenyloxycoumarin (7-IP), another natural prenyloxycoumain, exerted anti-inflammatory and neuroprotective effects against excitotoxicity; and (3) 4′-geranyloxyferulic acid (GOFA), a natural prenyloxycinnamic acid, also exerted anti-inflammatory effects. In the present study, using an intranigral lipopolysaccharide (LPS)-induced PD-like mouse model, we investigated whether AUR, 7-IP, and GOFA suppress microglial activation and protect against dopaminergic neuronal cell death in the SN. We successfully showed that these prenyloxyphenylpropanoids exhibited these prospective abilities, suggesting the potential of these compounds as neuroprotective agents for patients with PD.