A study suggests olive oleanolic acid may have therapeutic potential
Cristina G. Pedraz / DICYT The Unidad de Inmunidad Innata e Inflamación (a innate immune system and inflammation unit) in Valladolid has being working for eight years in a research area based on oleanolic acid’s potential (it is a triterpenoid distributed in the cuticles and leaves of olive trees) as an active ingredient to tackle the symptoms and sings of conditions strongly based on inflammatory processes such as multiple sclerosis (MS).
Led by researcher María Luis Nieto, this laboratory has published an important article in the British Journal of Pharmacology presenting the results of a study on mice having being infected with the disease. As the researcher explains, this line of work results from a collaboration with Dr. Ruiz-Gutierrez from Instituto de la Grasa (an institute for fat studies) and after Juliana Carvalho-Tavares, a Brazilian professor, stayed at the IBGM thanks to a grant from the Agencia Española de Cooperación Internacional para el Desarrollo (Aecid), a Spanish agency for international cooperation. “This professor was working on an experimental model of MS and, making use of her stay in the laboratory, we wanted to prove we were able to modulate the mechanism of action of the disease with the natural compounds we were working with”, she stated to DiCYT.
MS refers to a degenerative pathology of the central nervous system (CNS) in which the fatty myelin sheaths around the neurons are damaged through an inflammatory process. This results in an impaired patient, even in nerve impulses arrest, with an upshot of reduced mobility and even disability in severe cases. The scientific community believes that the disease has an autoimmune origin, that is, it arises from an inappropriate immune response of the body against cells and tissues present in the body.
In the study by IBGM, they used the best animal model available to study MS: experimental autoimmune encephalomyelitis (EAE), it is an inflammatory demyelinating disease of the CNS and it is used with rodents; it shares clinical, pathological and histopathological features with human MS. The ultimate goal, detailed María Luisa Nieto, is to search for new therapies against the disease.
“We used oleanolic acid treatment while the disease was induced in animals and we have also tried to initiate it preventively before it started to develop”, recounts the head of the research, adding that they have even studied the potential therapy “when the disease is already developed, in order to analyze different situations in the clinical practice”.
Researchers have found that even if it does not block the progression of the disease, it makes it develop more slowly. “The progression of the disease is considerably slower in animals when they are given the drug; moreover, we have been able to significantly reduce, even eliminate in some cases every inflammatory process related to the condition, which has an impact on the mice healing process from the pathological point of view”, as the researcher states.
Consequently, this study demonstrates the potential of oleanolic acid as a substance able to significantly reduce clinical signs (muscle control, weight, survival, etc.) and immune- inflammatory signs (changes in vascular permeability, leukocyte infiltration, cytokine presence) of EAE. The researchers have patented this new drug application and studies are underway at the cellular and molecular level: how these substances have an impact on the benefit produced in the disease. What is more, awaiting the pharmaceutical industry gets interested in this important development, they expect to contact with neurologists in order to bring the study to clinical practice.
The study of molecular mechanisms involved in the pathologies with inflammatory processes is the main line of work of the laboratory led by María Luisa Nieto. This work began when the researcher started writing her doctoral thesis and continued, in the IBGM, with the study of aspects related to inflammatory reactions. This area has led to the study of inflammation in the context of different diseases such as neoplasias, which were the first to be analyzed. Nowadays, the group is also working on the search for new possible therapeutic molecules as triterpene acid, found naturally in many plants. Therefore, they do research into the operation mechanism of these compounds at the cellular and molecular level in the inflammatory processes under study.
Successful Outcome in a Myocarditis Experimental Model
Due to the good results obtained with the therapy with oleanolic acid to reduce the effects of MS in the experimental model with mice, the IBGM research group came up with another study to prove that these compounds were actually well directed towards the neuroinflammatory disease or if this therapy could also be beneficial for other pathologies affecting other organs.
Thanks to their good relationship with the Instituto de Ciencias del Corazón (Icicor), an institute for heart studies, from the Hospital Clínico Universitario de Valladolid, led by Dr. Alberto San Román, the possibility of moving to a myocardial pathology research raised, specifically myocarditis, “a disease with a significant inflammatory process”. Myocardium is the muscle wall that covers the heart and myocarditis is an uncommon infection caused by virus, bacteria and fungi that triggers the inflammation process of the organ, among other aspects.
“This is also an autoimmune based disease and that is why we designed an experimental model on this pathology in order to determine if these compounds were equally effective as in the MS model”, the researcher reminds. After finishing studies in cell cultures, the team found that triterpene acids inhibit fibroblast proliferation unchaining programmed cell death. In addition, they could observe that these acids modulate cellular differentiation processes and restrain expression of inflammatory cytokines.
According to the IBGM laboratory leader, although studies on animals are still in course, “there is evidence that suggests that these compounds block the inflammatory response, that they are regulators of immune response and significantly enhance the course of the disease, since animals do not develop such an aggressive pathology”.
When this experimental stage comes to an end, “which is virtually complete”, the team will do research on the cardiac muscle at a cellular and molecular level to see if the therapeutic compounds are able to protect these cell types from an aggressive situation and to depict whether the triterpene acids act peripherally on the immune system cells. “If this happens, and they simply regulate the immune response, cardiac cells are not going to be affected”. Therefore, researchers would be able to make the difference between the cells that get damaged and those that get regulated. Finally, as in the experimental study on MS, the ultimate goal of this project is to get to do a clinical trial.
IBGM and Icicor researchers, who are part of the Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (Recava), a collaborative research thematic network on cardiovascular diseases, have filed a patent and are to publish the results. “We maintain a close collaboration with Icicor and a researcher trained in the group, Rubén Martín Montaña, has managed a Sara Borell contract at the institute so that the interaction with them is very sound”, she emphasizes.
María Luisa Nieto underlined that in the laboratory, they are looking for conditions that could be reflected into their basic research at al molecular and cellular level. “In the real world, these studies have many applications as there are many diseases with an inflammatory process involved”, she said. Consequently, since they began with this line of work, they have moved closer to human pathologies in which an application can be more or less effective. Tumors were one of the first conditions studied in the laboratory. Using cell culture studies of breast tumor lines, astrocytomas (a kind of brain tumor), among others, researchers proved the protective effect of olive oil triterpenes regarding cell growth.
“Many studies describe anti-inflammatory and protective properties of oleanolic acid, particularly from the cardiovascular point of view; these are wide range effect molecules. We work with the molecule extracted from plants, with the natural compound, but there are several studies that use synthetic compounds with added derivatives that make them more soluble or more active, for instance”, the researcher states.