The diuretic amiloride attenuates doxorubicin-induced chemobrain in rats: Behavioral and mechanistic study

Abstract

Cognitive impairment or "chemobrain" is a troublesome adverse effect which had been increasingly reported by cancer patients after doxorubicin (DOX) chemotherapy. Notably, Hypertension, a very common comorbidity in cancer patients, could pose a greater risk for negative cognitive outcomes. Amiloride (AML) is an antihypertensive, potassium-sparing diuretic that has been proven to be neuroprotective in different experimental models; this can be attributed to its ability to inhibit different ion transporters such as Na^+/H⁺ exchanger (NHE), which upon excessive activation can result in intracellular cationic overload, followed by oxidative damage and cellular death. Accordingly, this study was designed to investigate the potential neuroprotective effect of AML against DOX-induced chemobrain and to elucidate possible underlying mechanisms. Briefly, Histopathological examination and neurobehavioral testing (Morris water maze, Y maze and passive avoidance test) showed that AML co-treatment (10 mg/kg/day) markedly attenuated DOX (2 mg/kg/week)-induced neurodegeneration and memory impairment after 4 weeks of treatments. We found that DOX administration up-regulated NHE expression and increased lactic acid content in the hippocampus which were markedly opposed by AML. Moreover, AML mitigated DOX-induced neuroinflammation and decreased hippocampal tumor necrosis factor-α level, nuclear factor kappa-B, and cyclooxygenase-2 expression. Additionally, AML counteracted DOX-induced hippocampal oxidative stress as indicated by normalized malondialdehyde and glutathione levels. Furthermore, AML halted DOX-induced hippocampal apoptosis as evidenced by decreased caspase-3 activity and lower cytochrome c immunoexpression. Our results in addition to the previously reported antitumor effects of AML and its ability to mitigate cancer resistance to DOX therapy could point toward possible new repositioning scenarios of the diuretic AML especially regarding hypertensive cancer patients.

Keywords: Amiloride; Chemobrain; Doxorubicin; Hypertension; Na(+)/H(+)exchanger.