Vagus Nerve Stimulation Provides Neuroprotection Against Doxorubicin‐induced Chemobrain Via Activations of Both Muscarinic and Nicotinic Acetylcholine Receptors

Abstract

AbstractBackgroundChemotherapy, particularly treatment with doxorubicin (Dox), is known to cause neurotoxicity in the brain known as chemobrain. Dox administration causes neuroinflammation, mitochondrial dysfunction, and subsequent cognitive decline (1). Additionally, cancer survivors who received Dox were found to have an increased risk of developing dementia (2). Interestingly, the activation of the parasympathetic nervous system by vagus nerve stimulation (VNS) exerted neuroprotective effects on Alzheimer’s disease (3). However, the neuroprotective effects of VNS against Dox‐induced chemobrain have never been investigated. Moreover, whether the therapeutic effects of VNS are achieved via stimulation of nicotinic acetylcholine receptors (AChRs) or muscarinic acetylcholine receptors (mAChRs) needs further investigation.MethodTwenty male Wistar rats were divided into sham‐operated and VNS device‐implanted groups. After 2 weeks of recovery, all sham‐operated rats were divided and received either 0.9% NSS (Control; n = 4) or 3 mg/kg Dox for 6 doses (Sham; n = 4) via intraperitoneal injection. In addition, all VNS device‐implanted rats were treated with 3 mg/kg Dox for 6 doses and then randomly divided into 3 groups to receive either 0.9% NSS (VNS; n = 4), a mAChR antagonist (atropine; 1 mg/kg/day, VNS+Atro; n = 4), or a nAChR antagonist (mecamylamine; 7.5 mg/kg/day, VNS+Mec; n = 4). At the end of treatment protocol, cognitive function was assessed using the novel object location (NOL) task. The brains were obtained for further molecular studies.ResultDox treatment impaired cognitive performance in rats, as demonstrated by a decrease in the preference index in the NOL task (Figure A). Microglia in the CA1 region of Dox‐treated rats exhibited decreased process complexity and increased microglial volume, indicating reactivation of microglia (Figure B and C). Notably, Dox administration caused mitochondrial dysfunction in the brain, as evidenced by increased levels of mitochondrial reactive oxygen species (ROS) and mitochondrial membrane depolarization (Figure D and E). Importantly, the intervention with VNS rescued long‐term cognitive function in Dox‐treated rats by ameliorating all chemobrain pathologies (Figure A‐E). In contrast, the therapeutic effects of VNS were completely abolished by blocking either mAChRs or nAChRs using their antagonists (Figure A‐E).ConclusionThe findings suggested that VNS protected against Dox‐induced chemobrain through activations of both nAChRs and mAChRs.