Melatonin, metformin, and ranolazine equally improved cognitive function in rats with doxorubicin‐induced chemobrain

Abstract

Doxorubicin (Dox), the common therapeutic regimen for breast cancer treatment, has been shown the toxicity to the brain, known as "chemotherapy-induced cognitive impairment or chemobrain". However, the mechanisms of doxorubicin-induced chemobrain are not fully understood. Melatonin, metformin, and ranolazine have been shown the neuroprotective effects on mitochondrial function and cognition in several pathological conditions. However, the effects of melatonin, metformin, and ranolazine on peripheral oxidative stress, brain mitochondrial function, synaptic plasticity, and cognitive function in Dox-induced chemobrain has never been investigated. Forty male Wistar rats were randomly divided into two groups including control group (0.9% NSS, intraperitoneal (i.p.) injection, n=8) and Dox-treated group (3 mg/kg for 6 doses, i.p. injection, n=32). All Dox-treated rats were randomly divided into four subgroups (n=8/ subgroup) to receive either vehicle (0.9% NSS, daily oral gavage feeding), melatonin (10 mg/kg/day, oral gavage feeding), metformin (250 mg/kg/day, oral gavage feeding), or ranolazine (305 mg/kg/day, oral gavage feeding). Each drug was continuously given by starting at the 1st day of Dox for 30 days. At the end of experimental protocol, cognitive function was tested, and brains were obtained for further molecular investigation. Dox-treated rats significantly increased peripheral oxidative stress as indicated by increased serum malondialdehyde level, which were equally decreased by treatment with melatonin, metformin, and ranolazine (p<0.05, Figure 1). Moreover, brain mitochondrial dysfunction was demonstrated by increasing brain mitochondrial ROS production, membrane potential change, and swelling (p<0.05, Figure 1). These parameters were equally attenuated by all treatments. Consistently, Dox-treated rats showed synaptic dysplasticity, as indicated by decreasing dendritic spine density, which was attenuated by all treatments. Interestingly, melatonin, metformin, and ranolazine improved cognitive function in Dox-treated rats by increasing preference index of object in novel location and novel object in novel object location and recognition test (p<0.05, Figure 1). These findings suggest that melatonin, metformin, and ranolazine effectively ameliorate cognitive decline in rats with Dox-induced chemobrain. The novel findings obtained from the present study provides the therapeutic strategies which can be translated into clinical settings for better preventing chemobrain in the future.