Mitigating Methotrexate-Induced Kidney Damage in Mice by the Phragmanthera austroarabica Extract, Its Major Constituent, and Its Polymeric Nanoparticles

Phragmanthera austroarabica is known for its antioxidant and anti-inflammatory properties due to its high polyphenol content. Its chemical profile, analyzed via LC-ESI-TOF-MS/MS, revealed 28 compounds, including flavonoids, phenolics, and terpenes. This study examined the protective effects of the P. austroarabica crude extract, its major constituent gallic acid, and its polymeric nanoparticles (NPs) against methotrexate (MTX)-induced kidney toxicity in mice. Polymeric NPs were prepared using the nanoprecipitation technique to enhance efficacy. Kidney injury was induced by a single intraperitoneal dose of MTX (20 mg/kg), and mice were divided into six groups: control, MTX, and four cotreatment groups receiving MTX with the P. austroarabica extract, its NPs, gallic acid, or gallic acid NPs. The treatments lasted 10 days, starting 5 days before MTX injection. The extract, gallic acid, and their NPs improved renal function, inhibited MTX-induced renal tissue damage, reduced oxidative stress, enhanced antioxidant defenses (Nrf2/HO-1 upregulation), suppressed inflammation (downregulation of NF-κB, NLRP3, caspase-1, IL-1β, IL-6, and TNF-α and an increase in PPARγ), and prevented apoptosis (decreased Bax and caspase-3 and increased Bcl-2). These findings suggest that P. austroarabica and gallic acid NPs may serve as potential protective agents against MTX-induced nephrotoxicity.