N-acetylcysteine pharmacokinetics and neuroprotection in a translational ovarian cancer model of cancer-related cognitive impairment

Background: Platinum-based chemotherapy is part of the standard of care for ovarian cancer treatment, yet more than 70% of patients develop cancer-related cognitive impairment (CRCI) during and after treatment. Cisplatin-induced CRCI is associated with alterations in plasma cytokines, mitochondrial dysfunction, and glutathione depletion. In an ovarian cancer xenograft rat model, the antioxidant N-acetylcysteine (NAC; 250 mg/kg, i.p.) prevented cisplatin-induced CRCI. To inform a Phase 1 study of oral NAC for CRCI prevention in ovarian cancer patients, we compared oral and i.p. NAC administration on brain and blood glutathione, plasma cytokines, circulating NAC levels, and cognition in female rats with or without ovarian cancer. Methods: Female RNU rats bearing SKOV3.ip1 xenografts received cisplatin (5 mg/kg, i.p.) biweekly for four cycles with or without NAC (250 mg/kg/day, i.p.) administered for five days during each cycle, 10 hours after cisplatin. Cognitive testing (novel object recognition, NOR) was performed 6-7 weeks after treatment completion. For NAC pharmacokinetic studies, 70 female non-tumor-bearing Sprague Dawley rats were randomized to vehicle, 250 mg/kg NAC i.p., and 159, 212, 265, 370, 476 mg/kg oral NAC, with or without cisplatin. Plasma, whole blood, and brain tissue were collected 2 hours after one cycle, and plasma NAC levels were quantified by mass spectrometry. Results: Ovarian tumor-bearing rats treated with or without cisplatin (OvT+VEH, OvT+CDDP) showed reduced NOR discrimination ratios (≤0.5) compared with non-tumor-bearing controls (NT+VEH, P=0.0207). NAC prevented cisplatin-induced impairments in the NOR task (OvT+CDDP vs. OvT+CDDP+NAC, P=0.0343). Cisplatin significantly reduced hippocampal and frontal cortex glutathione levels within 48 h, which was prevented by 250 mg/kg NAC, i.p. administration. NAC did not alter cisplatin's anti-cancer activity or survival. Comparative analysis of plasma NAC levels after oral vs. i.p. administration is ongoing. Conclusions: NAC prevents cisplatin-induced CRCI in a clinically relevant ovarian cancer rodent model. Ongoing pharmacokinetic analyses will guide the design of a Phase 1 study of oral NAC in patients with ovarian cancer.