Acetylcholinesterase Inhibitor Exerted Neuroprotection Against Trastuzumab‐Induced Chemobrain

Abstract

AbstractBackgroundChemobrain has recently gained attention as a serious neurobehavioral consequence of chemotherapy in cancer patients. Even well‐recognized among conventional chemotherapeutic agents, trastuzumab (TRZ), an oncogene‐targeted therapy for treating breast cancer, has been shown to intricately caused symptoms of chemobrain elicited by impaired cerebral glucose metabolism and long‐term cognitive function. Noticeably, the inhibition of acetylcholinesterase using donepezil (DPZ), a medication widely used to treat Alzheimer’s disease (AD), possesses several pleiotropic effects including mitochondrial protection and immunomodulation. However, the mechanistic insights regarding the pathophysiology and therapeutic benefit of DPZ have never been holistically determined in a rat model of TRZ‐induced chemobrain.MethodFifteen male Wistar rats were randomized to receive either a 0.9% normal saline solution (Control; n=5) or 4 mg/kg of TRZ via intraperitoneal injection for 7 consecutive days. Then, TRZ‐treated rats were subdivided into 2 groups to receive either drinking water (TRZ, n=5) or 5 mg/kg of DPZ (TRZ+DPZ; n=5) via oral gavage as co‐treatment with TRZ for 7‐day duration. After cessation of the treatment paradigm, cognitive performance was assessed using the novel object location task (NOLT). The brain tissues were obtained for further molecular investigation.ResultTRZ‐treated rats showed impaired long‐term spatial memory as demonstrated by a reduction of preference index in the NOLT (Figure A). Systemic TRZ administration compromised mitochondrial anti‐oxidant capacity (Figure B) and potentiated the activation of mitochondrial‐fission related protein. Furthermore, the upregulation of neuroinflammation was observed in TRZ‐treated rats presented by increased TNF‐α mRNA level (Figure C) and microglial morphological changes into neurotoxic amoeboid‐shaped (Figure D). Additionally. Administration of TRZ triggered the phosphorylation of Tau protein (Figure E) and reduced dendritic spine density in CA1 region (Figure F). Strikingly, co‐administration with DPZ effectively rescued cognitive performance of TRZ‐treated rats by improving mitochondrial anti‐oxidant capacity, reducing mitochondrial fission, mitigating neuroinflammation and microglial polarization, attenuating Tau hyperphosphorylation, and preserving dendritic spine density (Figure A‐F).ConclusionThese findings suggested that DPZ exerted neuroprotective effects against TRZ‐induced chemobrain. Our findings pave the way for parasympathetic activation using DPZ as a therapeutic approach in the prevention of chemobrain in patients who received chemotherapy in the future.