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Melatonin, metformin, and ranolazine equally improved cognitive function in rats with doxorubicin‐induced chemobrain
Author(s) -
Chunchai Titikorn,
Ongnok Benjamin,
Pantiya Patcharapong,
Arinno Apiwan,
Khuanjing Thawatchai,
Prathumsap Nanthip,
Maneechote Chayadom,
Kerdphoo Sasiwan,
Jaiwongkam Thidarat,
Chattipakorn Nipon,
Chattipakorn Siriporn C
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.050172
Subject(s) - melatonin , medicine , metformin , oxidative stress , malondialdehyde , pharmacology , endocrinology , doxorubicin , neuroprotection , anesthesia , chemotherapy , diabetes mellitus
Background 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. Methods 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 1 st day of Dox for 30 days. At the end of experimental protocol, cognitive function was tested, and brains were obtained for further molecular investigation. Results 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). Conclusions 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.