Methotrexate (MTX) is one of the most commonly used chemotherapies for various types of cancer, including leukemia, breast cancer, hepatocarcinoma, and gastric cancers. However, the efficacy of MTX is frequently limited by serious side effects. Several studies have reported that the cytotoxic effect of MTX is not limited to cancer cells but can also affect normal tissues, leading to prospective damage to many organs. In the present study, we extensively investigated the molecular and microscopic basis of MTX-induced toxicity in different organs (liver, kidney, and heart) and explored the possible protective effect of pycnogenol, a polyphenolic component extracted from the bark of P. pinaster, to attenuate these effects. Biochemical analysis revealed that administration of MTX significantly reduced the function of the liver, kidney, and heart. Histological and immunohistochemical analysis indicated that MTX treatment caused damage to tissues of different organs. Interestingly, administration of pycnogenol (10, 20, and 30 mg/kg) significantly attenuated the deterioration effects of MTX on different organs in a dose-dependent manner, as demonstrated by biochemical and histological analysis. Our results reveal that pycnogenol successfully ameliorated oxidative damage and reduced toxicity, inflammatory response, and histological markers induced by methotrexate treatment. Taken together, this study provides solid evidence for the pharmacological application of pycnogenol to attenuate damage to different organs induced by MTX treatment.

Pycnogenol (PYC) is a plant-based extract derived from the proprietary bark of the French maritime pine (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. The standardized extract is composed of phenolic compounds (catechin, epicatechin, and taxifolin), condensed flavonoids (classed as procyanidins/ proanthocyanidins) and phenolic acids (cinnamic acids and other glycosides). these phenolic compounds after being ingested, undergo biotransformation and are broken down in the colon by microbial enzymes yielding smaller, bioavailable molecules that can then be absorbed by the colon into the bloodstream and transported to tissues and organs. The pycnogenol possess a highly protective characteristics versus various cardiovascular dysfunctions, kidney diseases, hepatic dysfunctions, neuro cognitive disorder, diabetes, reproductive dysfunction and infertility, cancer, digestive, retinal disease. The present review illustrates the effect of Pycnogenol as antioxidant and anti-inflammatory effects along with anti-tumor influence as well. Pycnogenol was concluded to act as an antioxidant agent in different situation including heart stress, cardiovascular system abnormalities, kidney disease and hepatic disorders, so it can be used in combination with other medication such as Methotrexate to abolish its side effects.