The beneficial health effects of Aspirin one of the oldest and the most commonly used medicines, have been quite a mystery to physicians. A recent study has now found that the main ingredient in aspirin targets the activities of an inflammatory protein associated with a wide variety of diseases. It has been discovered that aspirin’s main breakdown product, salicylic acid, blocks the protein, HMGB1, which could be the reason behind the drug’s therapeutic properties. It is hoped that this discovery could be instrumental in developing more powerful aspirin-like drugs. The results of the study were published in the journal Molecular Medicine.
The research was carried out by scientists at the Cornell University-affiliated Boyce Thompson Institute (BTI) in collaboration with colleagues at Rutgers and Italy’s San Raffaele University and Research Institute.
Daniel Klessig, a professor at BTI and Cornell University and study's senior author said that we have found out a key target of aspirin’s active form in the body – salicylic acid blocks the protein, HMGB1, which is associated with many prevalent diseases, like rheumatoid arthritis, heart disease, sepsis and cancers, like colorectal cancer and mesothelioma.
It has been known since long that aspirin blocks the enzymes cyclooxygenase 1 and 2, which produce hormone-like compounds that cause inflammation and pain, thereby giving a pain relieving effect. But, the body rapidly converts aspirin to salicylic acid, which is in effect, a less potent inhibitor of cyclooxygenase 1 and 2 than aspirin. Still, the effects of salicylic acid are same as aspirin, which suggests that salicylic acid may interact with additional proteins.
For the current study, the researchers studied the interaction between salicylic acid and HMGB1 by screening extracts prepared from human tissue culture cells to find proteins that could bind to salicylic acid. One of the proteins identified by them is HMGB1. The study has also identified a key suspect in neurodegenerative diseases like Alzheimer’s and Parkinson’s diseases, along with about two dozen additional candidates that have not been characterized yet.
Typically, HMGB1 is found inside the nucleus, but it can enter the blood stream when injured tissues or certain immune or cancer cells release it. The protein in the blood stream triggers inflammation by recruiting immune cells which prevents infections and repairs damaged tissues.
In order to find out more about the interactions between salicylic acid and HMGB1’s role in the body, Klessig worked with Marco Bianchi of San Raffaele University and Research Institute, who discovered that HMGB1 is a trigger of inflammation. They found that salicylic acid could block the recruitment and activation of immune cells at concentrations similar to those found in people on low-dose aspirin.
Bianchi said that they found that HMGB1 is involved in many disease conditions where the body confronts damage to its own cells. It's almost obvious that a very general anti-inflammatory compound blocks a very general inflammation trigger.
Klessig collaborated with biophysicist Gaetano Montelione at Rutgers to confirm that salicylic acid can bind to HMGB1, and also to identify the salicylic acid binding sites. They identified two derivatives of salicylic acid, which were found to be more effective than salicylic acid in blocking HMBG1’s pro-inflammatory activities. One of the compounds was synthesized in the lab, while the second one was isolated from a licorice plant – a Chinese medicinal herb.
Klessig said that they identified both synthetic and natural derivatives of salicylic acid which are about 50 to 1000 times more potent than salicylic acid or aspirin in suppressing the pro-inflammatory activity of extracellular HMGB1. This provides the proof of concept that more effective salicylic acid-based drugs are attainable.