Tissue acidosis as a bridge between ASIC1a acidotoxicity and pH-sensitive MRI in ischemic stroke

Tissue acidosis is a defining metabolic consequence of cerebral ischemia and a biologically active signal that may provide a physiological bridge between acid-sensing ion channel 1a (ASIC1a)-mediated acidotoxicity and pH-sensitive magnetic resonance imaging (MRI). During ischemia, impaired oxidative metabolism, enhanced glycolysis, lactate accumulation, and disrupted proton homeostasis produce intracellular and extracellular acid–base disturbances. Extracellular acidification activates ASIC1a-containing channels and can promote membrane depolarization, cation influx, and downstream injury signaling, while genetic deletion or pharmacological inhibition of ASIC1a reduces ischemic injury in experimental models. In parallel, amide proton transfer (APT) and related chemical exchange saturation transfer (CEST) MRI approaches provide pH-sensitive tissue contrast that may identify metabolically stressed and potentially salvageable ischemic tissue. Importantly, these approaches interrogate different biological scales: APT/CEST MRI characterizes a voxel-level tissue environment but does not directly measure ASIC1a expression, subunit composition, channel activity, or pharmacological target engagement. We therefore propose a framework in which tissue acidosis serves as the shared physiological link between these processes. Within this framework, pH-sensitive MRI identifies an acidotic tissue state in which ASIC1a-dependent injury may be biologically relevant, whereas direct genetic, pharmacological, electrophysiological, and biochemical approaches are required to establish ASIC1a dependence. A critical translational question is whether an imaging-defined acidotic but potentially salvageable tissue compartment preferentially benefits from ASIC1a inhibition. Testing this hypothesis through longitudinal multimodal imaging combined with direct ASIC1a manipulation and independent pH and metabolic measurements may establish whether pH-sensitive MRI can serve as a mechanistically informed biomarker for future ASIC1a-targeted neuroprotection in ischemic stroke.