Endothelial dysfunction predisposes spontaneously hypertensive stroke prone rats to spreading depolarization and spreading ischemia

• Applicant: Professor Dr. Jens P. Dreier
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413848220

Spreading depolarization (SD) is the generic term for waves of near-complete breakdown of neuronal transmembrane ion gradients causing cytotoxic edema in brain gray matter. The SD continuum ranges from short SDs in intact tissue to SDs of intermediate duration to terminal SD in severely ischemic tissue. SD induces either transient hyperperfusion in normal tissue (normal response); or severe hypoperfusion (inverse hemodynamic response=spreading ischemia) in tissue at risk. We previously found in patients with subarachnoid hemorrhage (SAH) that long-lasting spreading ischemias are observed when subdural optoelectrodes are located directly over newly developing delayed infarcts, suggesting that they cause these infarcts. In the previous project, we published the world's largest SD study, DISCHARGE-1, in 180 SAH patients. The previous project was translational. E.g., using DISCHARGE-1 data and based on principal component and path analyses, an important clinical finding was that SDs are a statistical mediator between subarachnoid blood volume and delayed infarct volume. In α2Na+/K+-ATPase (NaKA)-dysfunctional mice, a genetic model of Na+-sensitive hypertension, we found higher susceptibility to SD and a shift toward more inverse hemodynamic responses. We examined stroke-prone spontaneously hypertensive rats (SHRsp) to determine whether SD thresholds/hemodynamic responses are also altered in other genetic models of Na+ sensitivity and found that they are. Many SAH patients are iatrogenically exposed to intravenous hypertonic saline (HS), as this is currently considered a cost-effective option to control intracranial pressure (ICP) based on the osmotic properties of NaCl. One third of the population is Na+-sensitive. In the present project, our prospectively collected database of clinical, neuromonitoring, imaging and outcome data from 197 SAH patients, including >18,000 plasma Na+ values, will allow us to examine plasma Na+ in detail. In SHRsp and control rats (WKY), (i) we will continue a work package studying penumbral spreading ischemia pharmacologically and via deep phenotyping of the microcirculation using the novel technology of enhanced perfusion and O2 saturation (EPOS), (ii) will determine whether HS enhances spreading ischemia, particularly in SHRsp, and whether this might be related to α2NaKA dysfunction in SHRsp, and (iii) will examine whether HS opens the blood-brain barrier (BBB) to macromolecules but not to small molecules and yet leads to a delayed increase in brain interstitial Na+ by Na+ transport to the cerebrospinal fluid and glymphatic system. Our project builds on solid evidence from previous work that SD and spreading ischemia are of salient clinical importance and specifically addresses whether the common practice of ICP control with HS exacerbates spreading ischemia and BBB dysfunction, which may explain the poor outcome we see in our clinical data associated with high median plasma Na+ levels despite excellent ICP control.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Peter Martus