Modulation of mitochondrial dynamics rescues cognitive function in rats with ‘doxorubicin-induced chemobrain’ via mitigation of mitochondrial dysfunction and neuroinflammation

Abstract

Doxorubicin (DOX), an effective, extensively used chemotherapeutic drug, can cause cognitive deterioration in cancer patients. The associated debilitating neurological sequelae are referred to as chemobrain. Our recent work demonstrated that Dox treatment resulted in an imbalance in mitochondrial dynamics, ultimately culminating in cognitive decline in rats. Therefore, in this study, we aim to explore the therapeutic efficacy of a pharmacological intervention, which modulates mitochondrial dynamics using a potent mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promoter (M1) against Dox-induced chemobrain. In the study, male Wistar rats were randomly assigned to receive either normal saline solution or six doses of Dox (3 mg·kg−1) via intraperitoneal injection. Then, the Dox-treated rats were intraperitoneally given either 1% DMSO as the vehicle, Mdivi-1 (1.2 mg·kg−1), M1 (2 mg·kg−1), or a combined treatment of Mdivi-1 and M1 for 30 consecutive days. Long-term learning and memory were evaluated using the novel object location task and novel object recognition task. Following euthanasia, the rat brains were dissected to enable further molecular investigation. We demonstrated that long-term treatment with mitochondrial dynamic modulators suppressed mitochondrial fission in the hippocampus following Dox treatment, leading to an improvement in brain homeostasis. Mitochondrial dynamic modulator treatments restored cognitive function in Dox-treated rats by attenuating neuroinflammation, decreasing oxidative stress, preserving synaptic integrity, reducing potential Alzheimer's related lesions, and mitigating both apoptosis and necroptosis following Dox administration. Together, our findings suggested that mitochondrial dynamics modulators protected against Dox-induced cognitive impairment by rebalancing mitochondrial homeostasis and attenuating both oxidative and inflammatory insults.