Sympathetic Nervous System Hyperactivity as a Potential Key Mechanism Underlying Aneurysmal Subarachnoid Hemorrhage-Induced Vasospasm and Delayed Cerebral Ischemia

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH)-induced vasospasm and delayed cerebral ischemia (DCI) is the leading cause of morbidity and mortality in patients who survive the initial rupture event. Currently, mechanisms underlying vasospasm/DCI are not well understood. Thus, effective treatments remain elusive. While prior studies have focused on the role of disrupted intrinsic vascular mechanisms and vasoactive factors in mediating vasospasm/DCI, other potential contributors, such as the sympathetic nervous system (SNS), have been understudied. Recent clinical trials demonstrating stellate ganglion block efficacy in mitigating aSAH-induced DCI suggest an effect secondary to improved cerebral blood flow via reduced cerebrovascular tone, however, exact mechanisms underpinning these positive therapeutic results remain unclear. With consideration of prior clinical and preclinical observations, we hypothesized that during a DCI-associated timepoint in rats following aSAH, specific sympathetic regulatory brain regions would display increased neuronal activation.

Methods: Utilizing a cisterna magna model, male Sprague-Dawley rats (300-450 g) were injected with 0.1 ml/100g BW of autologous femoral arterial blood (SAH, n = 9) or saline (SHAM, n=11) at two timepoints 24 h apart. Rats underwent transcardial perfusion fixation 72 h after second injection. C-fos immunohistochemistry was performed and the following regions analyzed: paraventricular hypothalamic nucleus (PVN), supraoptic nucleus (SON), median preoptic nucleus (MnPO), rostral ventrolateral medulla (RVLM), and nucleus tractus solitarius (NTS). Unpaired t-tests were performed in PRISM.

Results: SAH animals demonstrated increased neuronal activation compared to SHAM controls in sympathetic centers: PVN (P=0.0197), SON (P=0.0036), and NTS (P=0.0477) with no difference found in RVLM (P=0.3127) and MnPO (P=0.8443).

Conclusion : These experiments establish relative activation of major SNS brain regions during vasospasm/DCI-associated timepoints following aSAH in rat models suggesting sympathoexcitation may play a key role in aSAH-induced DCI-related sequelae. Future studies characterizing neurochemical phenotypes of activated populations and to what extent these neurons contribute to DCI/vasospasm may ultimately uncover future therapeutic targets.