Neuroinflammation as a Target for Intervention in Subarachnoid Hemorrhage

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) is a sub-type of hemorrhagic stroke associated with the highest rates of mortality and long-term neurological disabilities. Despite the improvement in the management of SAH patients and the reduction in case fatality in the last decades, disability and mortality remain high in this population. Brain injury can occur immediately and in the first days after SAH. This early brain injury can be due to physical effects on the brain such as increased intracranial pressure, herniations, intracerebral, intraventricular hemorrhage, and hydrocephalus. After the first 3 days, angiographic cerebral vasospasm (ACV) is a common neurological complication that in severe cases can lead to delayed cerebral ischemia and cerebral infarction. Consequently, the prevention and treatment of ACV continue to be a major goal. However, most treatments for ACV are vasodilators since ACV is due to arterial vasoconstriction. Other targets also have included those directed at the underlying biochemical mechanisms of brain injury such as inflammation and either independently or as a consequence, cerebral microthrombosis, cortical spreading ischemia, blood–brain barrier breakdown, and cerebral ischemia. Unfortunately, no pharmacologic treatment directed at these processes has yet shown efficacy in SAH. Enteral nimodipine and the endovascular treatment of the culprit aneurysm, remain the only treatment options supported by evidence from randomized clinical trials to improve patients’ outcome. Currently, there is no intervention directly developed and approved to target neuroinflammation after SAH. The goal of this review is to provide an overview on anti-inflammatory drugs tested after aneurysmal SAH.

Calpastatin peptide attenuates early brain injury following experimental subarachnoid hemorrhage

“…Increases in arterial blood pressure and intracranial pressure, and decreases in cerebral blood flow, cerebral perfusion pressure and oxygen tension are observed in EBI (2)(3)(4). Cerebral inflammation, oxidative stress and neuronal apoptosis are involved in the pathogenesis of EBI following SAH (1,2,5,6). Previous clinical studies reported that the 120, 145 and 150 kDa fragments of the 280 kDa neuronal cytoskeletal protein α-II spectrin are elevated in the cerebrospinal fluid of patients with SAH, and revealed that these fragments are potential biomarkers for the severity of aneurysmal SAH (7)(8)(9)(10).…”

Plasma Periostin and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

“…Patients who survive an early stage of aneurysmal SAH and have their aneurysms obliterated are still at risk of delayed cerebral ischemia (DCI) that often results in severe disabilities or death [1][2][3]. The mechanisms of post-SAH brain injury are multifactorial, but neuroinflammation is considered as an important cause [4][5][6][7][8][9].…”

Inflammatory Responses Induced by the Rupture of Intracranial Aneurysms Are Modulated by miRNAs

“…Circulating HMGB1 can be released from various cells, including activated platelets [31,37]. The activation of platelets is a known phenomenon in SAH and is associated with early brain injury after SAH [3,38]. Thus, one can speculate that in the acute period after IA rupture, there is a tendency to decrease the production of HMGB1 in peripheral leukocytes; however, due to its release from other sources, including activated platelets, the plasma levels continue to rise.…”

“…The rupture of an intracranial aneurysm (IA) resulting in a subarachnoid hemorrhage (SAH) results in many systemic effects and strongly influences the functioning of the immune system. Alterations in inflammation-related protein levels in peripheral blood and in the number and activity of immune cells have been reported [1][2][3]. These changes are associated with the systemic consequences of IA rupture, including inflammatory responses and immunodepression, which might be critical for patient outcomes.…”