Minnelide

Abstract Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children. The current major therapy is hormones for most steroid-sensitive patients. However, many patients have recurrent relapses of the disease and require long-term immunosuppression, leading to significant morbidity due to the side effects of the drugs. Therefore, better drugs need to be urgently explored to treat nephrotic syndrome while avoiding the side effects of drugs. Minnelide, a water-soluble prodrug of triptolide, has been proved to be effective in treating cancers in many clinical trials. This study aimed to investigate the therapeutic effect of minnelide in mice with adriamycin (ADR) nephropathy, its underlying protection mechanisms, and its reproductive toxicity. Minnelide was administered intraperitoneally to 6–8-week female mice with adriamycin nephropathy for 2 weeks, and the urine, blood, and kidney tissues were taken to analyze the therapeutic effect. In addition, we evaluated reproductive toxicity by measuring the levels of gonadal hormones and observing the histological changes in ovaries and testes. Primary mouse podocytes were exposed to puromycin (PAN) to damage the cytoskeleton and induce apoptosis, and then, triptolide was used to evaluate the therapeutic effect and underlying protection mechanisms in vitro. It was observed that minnelide dramatically alleviated proteinuria and apoptosis in mice with adriamycin nephropathy. In vitro, triptolide ameliorated puromycin-induced cytoskeletal rearrangement and apoptosis via reactive oxygen species-mediated mitochondrial pathway. In addition, minnelide caused no reproductive toxicity to male and female mice. The results suggested that minnelide might be a promising drug for nephrotic syndrome.

Triptolide, a compound isolated from a Chinese medicinal herb, has potent antitumor, immunosuppressive, and anti-inflammatory properties. Due to its interesting structural features and diverse pharmacological activities, it has attracted great interest by the Society of Organic Chemistry and Pharmaceutical Chemistry. However, its clinical potential is greatly hampered by limited aqueous solubility and oral bioavailability, and multi-organ toxicity. In recent years, various derivatives of Triptolide have made varying degrees of progress in the treatment of inflammatory diseases, autoimmune diseases, and cancer. The most researched and potentially clinically valuable of them were (5R)-5-hydroxytriptolide (LLDT-8), PG490-88Na (F6008), and Minnelide. In this review, we provide an overview of the advancements made in triptolide and several of its derivatives' biological activity, mechanisms of action, and clinical development. We also summarized some prospects for the future development of triptolide and its derivatives. It is hoped to contribute to a better understanding of the progress in this field, make constructive suggestions for further studies of Triptolide, and provide a theoretical reference for the rational development of new drugs.