Silymarin Nanoparticles Counteract Cognitive Impairment Induced by Doxorubicin and Cyclophosphamide in Rats; Insights into Mitochondrial Dysfunction and Nrf2/HO-1 Axis

Abstract

Most cancer patients suffer cognitive impairment following chemotherapy, recognized as "chemobrain". Principally, doxorubicin and cyclophosphamide are frequently utilized conjointly for the treatment of several kinds of tumors. Silymarin was reported to possess anti-inflammatory, antioxidant, and neuroprotective impacts. The recent study shed light on the neuroprotective attributes of silymarin against cognitive dysfunction instigated in rats with doxorubicin/cyclophosphamide combination. Unfortunately, silymarin suffers reduced absorption following oral administration. Silymarin was formulated as a nanoemulsion to be administered intranasally. Male rats were allocated into six groups: control, doxorubicin (2 mg/kg, ip) and cyclophosphamide (50 mg/kg, ip), doxorubicin and cyclophosphamide + silymarin (200 mg/kg, oral), doxorubicin and cyclophosphamide + silymarin nanoemulsion (1 mg/kg, intranasal), silymarin (200 mg/kg, oral), and silymarin nanoemulsion (1 mg/kg, intranasal) groups, and treated for 21 days. The amount of silymarin reaching the brain was found to be enhanced following formulated nanoemulsion administration. Doxorubicin and cyclophosphamide caused behavioral, as well as memory deficits indicated by locomotor activity, y maze, and passive avoidance tests. Also, they induced histological alteration in hippocampi and the prefrontal cortices of rats. Besides, chemotherapy caused cognitive impairment assessed by acetylcholinesterase activity elevation. Additionally, caspase-3 augmentation and of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) pathway disturbance were found following chemotherapy treatment. Silymarin treatment opposed such effects via enhancing memory function, preserving brain architecture, and reducing acetylcholinesterase activity and caspase-3 level. Moreover, silymarin treatment improved mitochondrial biogenesis through activation Nrf-2/HO-1 axis. Collectively, silymarin nanoemulsion, at a 200-fold lower dose, can offer an innovative solution for cancer patients globally.