A polymer obtained as a bark exudate from the cashew tree (Anacardium occidentale) could become an important component of the treatment of gastroesophageal reflux disease, a condition that affects about 12% of the world’s population. The discovery was made in experiments conducted at the Federal University of Ceará (UFC) in Brazil.
Findings from the research project were presented by Marcellus Souza, a professor in UFC’s Department of Medicine and a former recipient of a PhD scholarship from FAPESP, during the Third International Symposium on Inflammatory Diseases (INFLAMMA III).
The event, which took place on June 21-23 in Ribeirão Preto (São Paulo State, Brazil), was organized by the Center for Research on Inflammatory Diseases (CRID) and the Brazilian Inflammation Society (SBIn).
“In tests performed on biopsied tissue from 33 patients, we observed that cashew tree gum adheres profoundly to esophageal cells, forming a biofilm and enhancing resistance to the damage caused by gastric acid. Our hypothesis is that in addition to affording topical protection the polymer also has anti-inflammatory effects,” Souza told Agência FAPESP.
The discovery was made possible by an experimental model that was developed at UFC to mimic the most prevalent form of the disease, non-erosive gastroesophageal reflux, in mice. The method is described in an article published on June 8 in the American Journal of Physiology.
“Between 60% and 70% of patients with reflux have the non-erosive phenotype of the disease,” Souza explained. “Although they present with symptoms such as heartburn, endoscopic examination doesn’t show any esophageal tissue damage.”
To mimic this condition in mice, the scientists performed a surgical procedure known as pylorus ligation to block the passage of stomach contents into the duodenum. They also sutured the distal portion of the stomach to prevent it from expanding.
“As a result, the stomach became full but was unable to expand, so its content flowed back into the esophagus,” Souza said. “Tissue inflammation peaked about three days after the procedure. It was also possible to observe enlargement of the spaces between esophageal cells, causing the epithelial barrier damage that’s characteristic of the disease.”
In one of the groups of mice, the researchers began treatment with purified cashew tree gum delivered by mouth shortly after the surgical procedure. They obtained the polymer thanks to a collaboration with researchers at the Federal University of Piauí (UFPI).
The animals received the treatment once a day for a week. They were then sacrificed so that their esophageal tissue could be analyzed and compared with the same tissue from untreated mice.
“Our results show that the cashew tree gum reduced edema and tissue permeability. In other words, by combating inflammation, the treatment kept the epithelial barrier intact and prevented gastric acid from crossing into the subepithelial region, where it could have activated receptors involved in the sensation of pain [heartburn],” Souza said.
In vitro tests with biopsied esophageal tissue from patients also showed reduced tissue permeability after treatment with cashew tree gum.
“At present, we’re performing toxicity studies to assess safety and to estimate the ideal dose, so that clinical trials can be conducted with the polymer in the future,” Souza said.
Novel therapeutic targets
Almost half of all patients who have the non-erosive form of gastroesophageal reflux disease fail to respond to conventional treatment, according to Souza. This consists of drugs in the proton pump inhibitor class, such as omeprazole and pantoprazole.
“So there’s a great need to develop new therapeutic methods,” he said. “To do so, we must understand why these patients feel pain even without having esophageal lesions.”
To understand the mechanisms involved in the sensation of pain, the group used the same experimental model to investigate the effect of gastroesophageal reflux on a cellular receptor known as TRPV1 (transient receptor potential vanilloid 1). Present in nerve cells, TRPV1 is a protein that acts as a sensory receptor, sending a signal that causes the perception of pain in response to a potentially damaging stimulus.
“Our results suggest that the augmented permeability of the epithelium in the esophagus due to the microinflammation that occurs in patients with non-erosive gastroesophageal reflux allows gastric acid to cross the epithelial barrier and activate this receptor, TRPV1, triggering a painful response,” Souza said.
To validate this hypothesis, the group treated the animals with TRPV1-blocking substances. In another experiment, molecules were administered to the mice to superstimulate the same receptor, causing the destruction of the sensory system that it modulates. In both cases, they observed a reduction in inflammation and esophageal permeability.
“So the data suggest that TRPV1 is a therapeutic target worth exploring for the treatment of non-erosive gastroesophageal reflux,” he concluded.
The third edition of INFLAMMA, held at the University of São Paulo’s Ribeirão Preto Law School (FDRP-USP), was attended by some 300 people.
“The symposium started small, as an activity to disseminate the work done by CRID, one of the Research, Innovation & Dissemination Centers (RIDCs) funded by FAPESP, but each year it attracts more researchers from all over Brazil. This edition had participants from Minas Gerais, Rio de Janeiro, Acre, Paraná, Santa Catarina and Ceará, as well as 22 speakers, eight of them from other countries,” said Fernando de Queiroz Cunha, a professor at the University of São Paulo’s Ribeirão Preto Medical School (FMRP–USP) and one of CRID’s principal investigators.
According to Cunha, the symposium may be held outside São Paulo in 2018 in order to foster even more interaction with researchers from other states.
Source : Agência FAPESP