Acetylcholinesterase inhibitor provides neuroprotective effects against doxorubicin‐induced chemobrain

Abstract

Chemobrain has recently been recognized as the most common neurological consequences following chemotherapy, particularly doxorubicin (Dox) treatment. In addition, the incidence of Alzheimer's disease (AD) increases in response to chemotherapy. Dox administration induced cognitive impairment via brain oxidative stress, neuroinflammation, mitochondrial dysfunction, cholinergic deficits, and cumulating neuronal apoptosis. Notably, donepezil (DPZ), an acetylcholinesterase inhibitor, has been proven to effectively attenuate various neuropathological conditions, particularly AD. However, the mechanistic insight regarding the protective effects of DPZ on cognition and brain pathologies in rats with doxorubicin-induced chemobrain has never been determined. Fifteen male Wistar rats were randomized to receive either a 0.9% normal saline solution (Control; n=5) or 3 mg/kg Dox for 6 doses via intraperitoneal injection. Then, Dox-treated rats were divided into 2 groups to receive either vehicle (Dox, n=5) or DPZ (5 mg/kg: Dox+DPZ; n=5) orally, starting at 1st day of Dox for a 30-day duration. After completion of the treatment paradigm, cognitive function was evaluated using the novel object location (NOL) task. The brains were obtained for further molecular investigation. Dox-treated rats exhibited impaired cognitive performance as presented by a decline in preference index in the NOL test. Loss of dendritic spines was observed following Dox treatment. Dox-treated rats showed brain mitochondrial dysfunction as indicated by increased mitochondrial reactive oxygen species (ROS) production (Figure 1) and imbalanced mitochondrial dynamics. Additionally, Dox induced neuroinflammation as demonstrated by increased TNF-α mRNA expression, together with enhanced microglial activation (Figure 1). Interestingly, Dox-treated rats developed potential amyloid lesions (Figure 1) and disrupted neurogenesis in the hippocampus which in turn led to neuronal cell death through both apoptosis and necroptosis. Strikingly, DPZ co-treatment completely restored cognitive function (Figure 1) by reducing dendritic spine loss, improving mitochondrial function, balancing mitochondrial dynamics, ameliorating neuroinflammation, decreasing Alzheimer's related proteins, preserving neurogenesis, and inhibiting apoptosis and necroptosis. These findings suggested that DPZ provided neuroprotection against Dox-induced chemobrain, which could be used for the therapeutic approach to prevent chemobrain in patients who received chemotherapy in the future.