Patho-Pharmacological Research of Anti-allergic Natural Products Targeting Antihistamine-Sensitive and -Insensitive Allergic Mechanisms.

Histamine H1 receptor (H1R) has a special up-regulation mechanism by the stimulation of H1R, mediated by protein kinase C-delta (PKCδ) signaling and H1R gene expression, resulting increase in H1R signaling. Increase in H1R mRNA in nasal mucosa was induced after the provocation of nasal hypersensitivity model rats and suppressed by the pre-treatment of antihistamines. Improvement of nasal symptoms and suppression of H1R mRNA expression in nasal mucosa were also observed by the pre-treatment of antihistamines in pollinosis patients. Elucidation of a correlation between symptoms and H1R mRNA level suggests that H1R gene is an allergic disease (AD)-susceptibility gene, targeted by antihistamines. Similar to antihistamines, pre-treatment of Kujin extract, an anti-allergic Kampo medicine improved nasal symptoms and suppressed H1R mRNA expression in nasal hypersensitivity model rats. (-)-Maackiain targeting heat shock protein 90 (Hsp90) was isolated as an inhibitor of PKCδ signaling-mediated H1R gene expression from Kujin extract. In addition to H1R-mediated activation of H1R gene expression as the first mechanism, nuclear factor of activated T-cells (NFAT)-mediated IL-9 gene expression is suggested to participate to allergic symptoms as the second mechanism insensitive to antihistamines. Pyrogallol and proanthocyanidin suppressing IL-9 gene expression were discovered from Awa-tea and lotus root knots, respectively. Combination therapy using medicines suppressing both H1R gene expression and IL-9 gene expression is promising for outstanding alleviation of AD. Multifactorial diseases involving H1R gene expression may be treated by the combination therapy with antihistamine and complementary drugs, and diseases involving PKCδ signaling may be treated by drugs targeting Hsp90.