Transcranial Direct Current Stimulation Attenuates Ischemic Stroke-Induced Autonomic and Behavioral Dysfunction via a RAS-Autophagy-Iron Axis in the Brainstem.

Ischemic stroke frequently results in sympathetic overactivity and blood pressure dysregulation, primarily due to impaired central autonomic regulation within the rostral ventrolateral medulla (RVLM) in the brainstem. However, the molecular mechanisms underlying this dysfunction remain insufficiently defined. In this study, we examined the regulatory interplay between the renin-angiotensin system (RAS), autophagy, and iron metabolism in the RVLM in a transient middle cerebral artery occlusion model (MCAO) of ischemic stroke in Sprague-Dawley rats. Our results revealed that stroke induced an imbalance in RAS pressor and depressor signaling, disrupted autophagic flux, and altered iron storage protein expression. These molecular abnormalities were accompanied by elevated blood pressure and suggest a mechanistic link to sympathetic dysregulation. Notably, transcranial direct current stimulation (tDCS) mitigated these stroke-induced abnormalities by downregulating RAS pressor signaling, restoring impaired autophagic activity-including autophagic ferritin degradation-and consequently reducing iron accumulation-associated oxidative stress in the RVLM. Collectively, our findings propose a putative molecular cascade contributing to post-stroke sympathetic overactivity and highlight non-invasive tDCS as a potential neuromodulatory intervention to restore neurochemical homeostasis in the RVLM.