Allopurinol alleviates estrogen and progesterone-induced mammary gland hyperplasia through targeting PI3K/AKT/mTOR and Ki-67 pathways in female rats

Background and Purpose: Despite being widely used, there is no study on the effects of allopurinol on mammary gland hyperplasia (MGH). In this work, we elucidate the efficacy of allopurinol in alleviating MGH induced in female rats by estrogen and progesterone and exploring the underlying mechanisms. Experimental approach: Female Wistar rats were allocated into three groups (n=10). Control group administered carboxymethyl cellulose (CMC) 1% orally. Rats in both MGH and MGH+allopurinol groups injected with 0.5 mg/kg/day estrogen (IM) for 25 days followed by 0.5 mg/kg/day progesterone (IM) for 5 days. On the 31st day of the experiment, only MGH+allopurinol group was treated daily with allopurinol 50 mg/kg orally for 30 days. Oxidative stress, inflammatory parameters and PI3K/AKT/mTOR genes expression were measured. Histological and immunohistochemical analysis were performed. Key Results: In MGH group, there was significant decrease in tissue Nrf2, SOD and CAT levels and significant increase in tissue MDA and NO levels. Moreover, tissue NF-κB, TNF-α, IL-6 levels were significantly elevated, while tissue IL-10 level was significantly reduced. Mammary PI3K, AKT and mTOR genes were positively regulated. Histologically and immunohistochemically there were proliferative changes including hyperplasia in most lobules, increased number of ducts, acini, and multilayered epithelial lining, and increased expression of Ki-67. Whereas treatment with allopurinol significantly reversed the abnormal biochemical and histological abnormalities. Moreover, restored the expression of PI3K/AKT/mTOR pathway and decreased the expression of Ki-67. Conclusion & Implication: Therefore, results demonstrated that allopurinol could alleviate estrogen and progesterone-induced mammary gland hyperplasia through targeting PI3K/AKT/mTOR and Ki-67 pathways.