5-6-2--3--5--6--hexamethoxyflavone and Disease-Models--Animal

We have recently shown that 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) and auraptene (AUR) have neuroprotective effects on the central nervous system. HMF, a citrus flavonoid, altered NMDA-type glutamate receptor antagonist MK-801-induced memory dysfunction and schizophrenia-positive symptom-like behavior. HMF also showed a protective effect against ischemia-induced short-term memory dysfunction. In the ischemic brain, HMF induced the following protective effects against brain dysfunction: 1) rescue of neuronal cell death in the hippocampus; 2) increased production of brain-derived neurotrophic factor; 3) stimulation of neurogenesis in the dentate gyrus subgranular zone; 4) activation of the autophosphorylation of calcium-calmodulin-dependent protein kinase II; and 5) suppression of microglial activation. On the other hand, AUR, a citrus coumarin, ameliorated lipopolysaccharide-induced inflammation in the brain as shown by inhibition of microglial activation and inhibition of cyclooxygenase (COX)-2 expression in the hippocampus. AUR also showed antiinflammatory effects on the ischemic brain by inhibiting microglial activation, COX-2 expression, and neuronal cell death in the hippocampus. The peel of kawachibankan (Citrus kawachiensis), a noted citrus product of Ehime prefecture, Japan, contains AUR, HMF, naringin, and narirutin. The dried powder of both the peel and juice had antiinflammatory effects in the mouse hippocampus, suggesting that citrus compounds may be beneficial as neuroprotective agents in the treatment of neurological disorders.

Topics: Animals; Anti-Inflammatory Agents; Brain; Brain Ischemia; Brain-Derived Neurotrophic Factor; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Death; Central Nervous System; Citrus; Coumarins; Cyclooxygenase 2; Disease Models, Animal; Flavones; Food; Hippocampus; Humans; Memory Disorders; Mice; Microglia; Nervous System Diseases; Neurogenesis; Neuroprotective Agents; Phytotherapy; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Chemotherapy with an anticancer agent generally causes gastrointestinal tract disorders such as vomiting and anorexia, but the mechanism remains unclear. Rikkunshito, a kampo preparation, is known to alleviate such adverse reactions. In this study, we attempted to clarify the mechanism.. We investigated the decreases of plasma acylated-ghrelin level and food intake caused by cisplatin, serotonin (5-HT), 5-HT agonists, and vagotomy as well as the decrease-suppressing effects of rikkunshito and 5-HT antagonists. In addition, binding affinities of rikkunshito components were determined in receptor-binding assays using 5-HT2B and 5-HT2C receptors.. Cisplatin, 5-HT, BW723C86 (5-HT2B-receptor agonist), and m-chlorophenylpiperazine HCl (5-HT2C agonist) markedly decreased plasma acylated-ghrelin levels, although 5-HT3 and 5-HT4 agonists had no effect. In contrast, 5-HT2B and 5-HT2C antagonists suppressed the cisplatin-induced decrease of plasma acylated-ghrelin level and food intake. Administration of rat ghrelin improved the cisplatin-induced decrease in food intake. Vagotomy decreased the plasma acylated-ghrelin level, which was decreased further by cisplatin. Rikkunshito suppressed such cisplatin-induced decreases of plasma acylated-ghrelin level and food intake. The suppressive effect of rikkunshito was blocked by a ghrelin antagonist. Components of rikkunshito, 3,3',4',5,6,7,8-heptamethoxyflavone, hesperidin, and iso-liquiritigenin showed a 5-HT2B-antagonistic effect in vitro, and oral administration of rikkunshito suppressed the cisplatin-induced decrease in the plasma acylated-ghrelin level.. The cisplatin-induced decreases of the plasma acylated-ghrelin level and food intake are mediated by 5-HT2B/2C receptors and suppressed by flavonoids in rikkunshito.

Topics: Acylation; Aminopyridines; Animals; Anorexia; Antineoplastic Agents; Body Weight; Chalcones; Cisplatin; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Eating; Flavones; Gastric Mucosa; Gastrointestinal Agents; Ghrelin; Hesperidin; Indoles; Male; Oligopeptides; Piperazines; Protein Binding; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Ghrelin; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Stomach; Thiophenes; Vagotomy