Complex Interactions between Phytochemicals. The Multi-Target Therapeutic Concept of Phytotherapy

Abstract

Drugs derived from natural resources represent a significant segment of the pharmaceutical market as compared to randomly synthesized compounds. It is a goal of drug development programs to design selective ligands that act on single disease targets to obtain highly effective and safe drugs with low side effects. Although this strategy was successful for many new therapies, there is a marked decline in the number of new drugs introduced into clinical practice over the past decades. One reason for this failure may be due to the fact that the pathogenesis of many diseases is rather multi-factorial in nature and not due to a single cause. Phytotherapy, whose therapeutic efficacy is based on the combined action of a mixture of constituents, offers new treatment opportunities. Because of their biological defence function, plant secondary metabolites act by targeting and disrupting the cell membrane, by binding and inhibiting specific proteins or they adhere to or intercalate into RNA or DNA. Phytotherapeutics may exhibit pharmacological effects by the synergistic or antagonistic interaction of many phytochemicals. Mechanistic reasons for interactions are bioavailability, interference with cellular transport processes, activation of pro-drugs or deactivation of active compounds to inactive metabolites, action of synergistic partners at different points of the same signalling cascade (multi-target effects) or inhibition of binding to target proteins. "-Omics" technologies and systems biology may facilitate unravelling synergistic effects of herbal mixtures.

Piper sarmentosum Roxb. produces antidepressant-like effects in rodents, associated with activation of the CREB-BDNF-ERK signaling pathway and reversal of HPA axis hyperactivity

“…These diseases are not regulated by a single molecular target but caused by multi-factorial, and there are often multiple ways or alternate processes that may be switched on in response to the inhibition of a specific target (Home et al, 2009;Rather et al, 2013), for which a new technical term polypharmacology has been proposed (Efferth and Koch, 2011;Xie et al, 2012). Depression is one of these multi-target diseases, and various hypothesis or protein factors participate in its pathogenesis, such as monoaminergic hypothesis, HPA axis hypothesis, BDNF, CREB and ERK signaling pathways.…”

Synergistic Interactions in Natural Products: Therapeutic Potential and Challenges

“…8 Em contraste com o metabolismo primário, relacionado a processos de crescimento e obtenção de energia, comuns a todos os seres vivos, o metabolismo secundário relaciona-se à produção de substâncias envolvidas na defesa contra predadores e agentes patogênicos e na atração de agentes polinizadores. 8,23,24 Como as plantas são sésseis, estas desenvolveram um diversificado arsenal químico, através do qual interagem com o meio e se defendem contra ameaças. Portanto, os metabólitos secundários surgiram como resultado da interação dos vegetais com o ambiente e evoluíram ao longo de 140 milhões de anos.…”

“…Esquema de estratégia clássica para a descoberta de novos medicamentos a partir de produtos naturais Exemplos mais recentes de fármacos de origem vegetal incluem a galantamina (1), a artemisinina (2) e o taxol (3), utilizados no tratamento de doença de Alzheimer, malária e câncer, respectivamente (Figura 3). [7][8][9][10] Entretanto, frequentemente, os processos de fracionamento e purificação de extratos vegetais levam à redução ou perda da atividade biológica inicialmente observada. É igualmente frequente a constatação de que misturas complexas de substâncias de origem natural produzem efeitos mais pronunciados que doses proporcionais de seus constituintes isolados.…”

“…Não é surpreendente, portanto, que misturas destes agentes, ao atuar sobre diversos alvos, produzam efeitos mais potentes que uma única substância. 5,6,8,19 Enquanto na estratégia terapêutica ainda dominante são empregadas, isoladamente, substâncias de origem sintética ou natural, na fitoterapia são utilizados extratos de uma única espécie ou combinações de extratos. [19][20][21] Portanto, os novos paradigmas, que favorecem esquemas terapêuticos de múltiplos componentes, poderão impulsionar a pesquisa e desenvolvimento de fitoterápicos.…”

Current issues and perspectives in herbal hepatotoxicity: a hidden epidemic

“…Mechanistic reasons for interactions are bioavailability, interference with cellular transport processes, activation of pro-drugs or deactivation of active compounds to inactive metabolites, action of synergistic partners at different points of the same signalling cascade (multi-target effects) or inhibition of binding to target proteins. [3]. All of these are important clues whose definite biological effects are impossible to control entirely.…”