RESUMO
Bergenin (1), a unique fused C-glycoside isolated from Bergenia species, possesses interesting anti-inflammatory and antipain activities. To study SAR of this scaffold, first-generation derivatives were synthesized and evaluated for inhibition of lymphocyte proliferation and production of pro-inflammatory cytokines. The C-7 substituted derivatives showed inhibition of IL-6 as well as TNF-α production. Bergenin and its most potent IL-6 inhibitor derivatives 4e and 4f were then investigated in a panel of in vitro and in vivo inflammation/arthritis models. These compounds significantly decreased the expression of NF-kB and IKK-ß in THP-1 cells. In in vivo study in BALB/c mice, a dose-dependent inhibition of SRBC-induced cytokines, reduction in humoral/cell-mediated immunity, and antibody titer was observed. The CIA study in DBA/1J mice indicated that compounds led to reduction in swelling of paws, cytokine levels, and anticollagen IgG1/IgG2a levels. The significant in vivo immunosuppressive efficacy of pyrano-isochromanones demonstrates the promise of this scaffold for development of next-generation antiarthritic drugs.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Benzopiranos/química , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Cromanos/química , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Quinase I-kappa B/química , Quinase I-kappa B/metabolismo , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina G/metabolismo , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição , Fator de Necrose Tumoral alfa/biossínteseRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Leaves of Cassia alata (family: Caesalpiniaceae) are ethnomedically claimed as anti-asthmatic. In the current study we aimed to investigate the anti-allergic activities of hydro-methanolic extract of Cassia alata (Linn.) and its constituents rhein and kaempferol on triple antigen/sheep serum-induced mast-cell degranulation in rats. MATERIALS AND METHODS: Antiallergic activity of hydroalcoholic extract of Cassia alata along with its two components rhein and kaempferol was evaluated using in vivo mast cell stabilization assay. Inhibitory effect on lipoxygenase (LOX) enzyme was also evaluated in vitro. Further chemical standardization of Cassia alata extract was done using rhein and kaempferol by HPTLC-densitometric method. RESULTS: The hydroalcoholic extract of Cassia alata significantly inhibited mast cell degranulation at 200mg/kg dose. Both chemical constituents rhein and kaempferol also showed potent (>76%) inhibition of mast-cell degranulation at 5mg/kg. Extract and rhein inhibited LOX enzyme with IC(50) values of 90.2 and 3.9µg/mL, respectively, whereas kaempferol was inactive. CONCLUSION: Our results suggest that Cassia alata exhibit anti-allergic activity through mast cell stabilization and LOX inhibition. Thus, Cassia alata or its active constituents could be potential alternative treatment for allergic diseases.
