Elucidating novel mechanisms of brain injury following subarachnoid hemorrhage: an emerging role for neuroproteomics

Abstract

Subarachnoid hemorrhage (SAH) is a devastating neurological injury associated with significant patient morbidity and death. Since the first demonstration of cerebral vasospasm nearly 60 years ago, the preponderance of research has focused on strategies to limit arterial narrowing and delayed cerebral ischemia following SAH. However, recent clinical and preclinical data indicate a functional dissociation between cerebral vasospasm and neurological outcome, signaling the need for a paradigm shift in the study of brain injury following SAH. Early brain injury may contribute to poor outcome and early death following SAH. However, elucidation of the complex cellular mechanisms underlying early brain injury remains a major challenge. The advent of modern neuroproteomics has rapidly advanced scientific discovery by allowing proteome-wide screening in an objective, nonbiased manner, providing novel mechanisms of brain physiology and injury. In the context of neurosurgery, proteomic analysis of patient-derived CSF will permit the identification of biomarkers and/or novel drug targets that may not be intuitively linked with any particular disease. In the present report, the authors discuss the utility of neuroproteomics with a focus on the roles for this technology in understanding SAH. The authors also provide data from our laboratory that identifies high-mobility group box protein-1 as a potential biomarker of neurological outcome following SAH in humans.

Figure 1

(A) Representative Western blot of HMGB1 in CSF samples collected from aneurysmal SAH (Lanes #1-5) or a normal pressure hydrocephalus (NPH) control patient (Lane #6). Blots were imaged using a Li-Cor Odyssey near-infrared imaging system. SAH patients consistently presented with a ~25 kDa band corresponding to HMGB1, whereas NPH patients did not show a clear band. (B) Non-contrast CT scan (axial view) of a 45-year old woman with a Hunt and Hess 3, Fisher 4 score. Patient was sleepy and confused following a ruptured left posterior communicating artery aneurysm. Patient sample is depicted in Lane #2. (C) Non-contrast CT scan (axial view) of a 77-year old woman with a Hunt and Hess 4, Fisher 4 score. Patient was stuporous with significant right hemiparesis following a ruptured left middle cerebral aneurysm. Patient sample is depicted in Lane #5.

Figure 2

Retrospective correlation analysis of HMGB1 content within the CSF of SAH patients with (A) Hunt-Hess Scale grade, (B) Fisher Scale grade, and (C) modified Rankin Scale grade at follow up examination. HMGB1 was quantified by Western blotting. All grades were provided by the attending physician, who was blinded to experimental studies. HMGB1 was not present in the CSF of control normal pressure hydrocephalus (NPH) patients.