Delayed cerebral ischemia (DCI) remains a challenging but very important condition, because DCI is preventable and treatable for improving functional outcomes after aneurysmal subarachnoid hemorrhage (SAH). The pathologies underlying DCI are multifactorial. Classical approaches to DCI focus exclusively on preventing and treating the reduction of blood flow supply. However, recently, glutamate-mediated neuroelectric disruptions, such as excitotoxicity, cortical spreading depolarization and seizures, and epileptiform discharges, have been reported to occur in high frequencies in association with DCI development after SAH. Each of the neuroelectric disruptions can trigger the other, which augments metabolic demand. If increased metabolic demand exceeds the impaired blood supply, the mismatch leads to relative ischemia, resulting in DCI. The neuroelectric disruption also induces inverted vasoconstrictive neurovascular coupling in compromised brain tissues after SAH, causing DCI. Although glutamates and the receptors may play central roles in the development of excitotoxicity, cortical spreading ischemia and epileptic activity-related events, more studies are needed to clarify the pathophysiology and to develop novel therapeutic strategies for preventing or treating neuroelectric disruption-related DCI after SAH. This article reviews the recent advancement in research on neuroelectric disruption after SAH.

Aneurysmal subarachnoid hemorrhage (aSAH) causes serious brain injury, and its mechanisms have not been completely unraveled so far. The causative factors for the brain injury initiated by an aneurysm rupture, which is referred to as the early brain injury (EBI), include elevated intracranial pressure, cerebral hypoperfusion, and blood contents that are directly exposed to the brain surface. At Day 4–14 post aSAH, delayed cerebral ischemia (DCI) often develops, which may worsen the neurological outcomes critically. DCI may be a consequence of EBI. Understanding the complex mechanisms underlying the post-aSAH brain injury (EBI and DCI) is, therefore, important in order to improve the neurological outcomes. In addition, several biomarkers possibly associated with EBI, DCI, and neurological outcome have been investigated, although none of these has been conclusive. A matricellular protein periostin has emerged as an important potential contributor to EBI and DCI, and may serve as the biomarker and a therapeutic molecular target for EBI and DCI. In the present report, the possible role of periostin in aSAH has been reviewed.

Osteopontin (OPN), a matricellular protein, is produced as a full-length OPN (FL-OPN) and cleaved by thrombin, thus generating the N-terminal half of OPN (OPN N-half) with new functions. Although plasma FL-OPN levels have been associated with neurovascular events after aneurysmal subarachnoid hemorrhage (SAH), plasma OPN N-half levels have never been investigated. In this study, prospective clinical data and plasma samples were collected from 108 consecutive SAH patients with ruptured aneurysms undergoing acute treatment via surgery, and FL-OPN and OPN N-half levels were measured in plasma with a particular focus on delayed cerebral infarction (DCIn), which has the greatest impact on outcomes. Plasma FL-OPN and OPN N-half levels were intercorrelated and significantly higher in patients with DCIn at days 10–12 post-SAH; a greater area under the receiver-operating characteristic curve was observed for OPN N-half levels, with a cut-off value of 70.42 pmol/L. Multivariate analyses revealed that plasma OPN N-half levels of ≥70.42 pmol/L at days 10–12 were independently associated with DCIn development (adjusted odds ratio, 5.65; 95% confidence interval, 1.68–18.97; p = 0.005). Based on the findings of this study and previous reports, an increase in the OPN N-half level may be indicative of a protective mechanism against DCIn development, and, thus, it holds promise as a new therapeutic target against DCIn after aneurysmal SAH.