Neuroinflammation as a Target for Intervention in Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) is a stroke subtype that affects, preponderantly, young adults. This condition carries a mortality of approximately 30-50% and a rate of permanent neurological disability of 30%. In addition, a substantial number of patients with an apparent good outcome suffer from residual neurocognitive impairment which, though subtle, prevents them from returning to work and having a normal life. Based on these data, it has been estimated that SAH is responsible for almost a quarter of all the years lost because of stroke. The calcium channel blocker nimodipine remains the only pharmacological treatment for SAH. This drug, however, has limited effectiveness and its use in clinical practice may be limited due to hypotension. Therefore, novel and effective treatments for this condition are desperately needed. The outcome in SAH has been associated with early brain injury, vasospasm, and delayed cerebral ischemia. Mechanistically, these processes are characterized by micro- and macro-vascular dysfunction, microthrombi formation, blood-brain barrier (BBB) dysregulation, brain edema, and neural-cell survival. Soon after SAH, there is a robust inflammatory response characterized by pyrexia, leukocytosis, and upregulation of adhesion molecules and cytokines in the periphery and in the CNS. Observational studies have shown that patients with more severe inflammatory responses experience worse outcomes after SAH. At the molecular level, different proinflammatory intracellular signaling pathways, including mitogen-activated protein-kinase and nuclear factor kappa-β, are activated in cerebral vessels after experimental SAH and their inhibition has been shown to decrease the occurrence of vasospasm. In addition, clinical and preclinical data have linked cytokine upregulation (interleukins [IL]-1B, IL-6 and IL-8, tumor necrosis factor-α, and monocyte chemoattractant protein-1), enhanced expression of adhesion molecules (selectins, integrins, and ICAM), and neutrophil activation to vasospasm of large cerebral arteries, microvascular dysregulation, and cell death. Moreover, immune cells regulate hemostasis and secrete active proteases, including matrix metalloproteinase 9, which promote microthrombosis and induce blood brain barrier dysfunction, respectively. In this context, it has been suggested that an enhanced inflammatory burden might contribute to brain injury in SAH through numerous downstream mechanisms. On the other hand, growing evidence demonstrates that neuroinflammation may influence the proliferation and migration of progenitor cells that participate of synaptic plasticity, neurogenesis, and neurorepair.