Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase‐9 inhibition

Abstract

ObjectiveDelayed cerebral ischemia (DCI) is an independent risk factor for poor outcome after aneurysmal subarachnoid hemorrhage (SAH) and is multifactorial in etiology. While prior studies have suggested a role for matrix metalloproteinase‐9 (MMP‐9) in early brain injury after SAH, its contribution to the pathophysiology of DCI is unclear.MethodsIn the first experiment, wild‐type (WT) and MMP‐9−/− mice were subjected to sham or endovascular perforation SAH surgery. In separate experiments, WT and MMP‐9−/−mice were administered vehicle or minocycline either pre‐ or post‐SAH. All mice underwent assessment of multiple components of DCI including vasospasm, neurobehavioral function, and microvessel thrombosis. In another experiment, rabbits were subjected to sham or cisterna magna injection SAH surgery, and administered vehicle or minocycline followed by vasospasm assessment.Results MMP‐9 expression and activity was increased after SAH. Genetic (MMP‐9−/− mice) and pharmacological (pre‐SAH minocycline administration) inhibition of MMP‐9 resulted in decreased vasospasm and neurobehavioral deficits. A therapeutically feasible strategy of post‐SAH administration of minocycline resulted in attenuation of multiple components of DCI. Minocycline administration to MMP‐9−/− mice did not yield additional protection. Consistent with experiments in mice, both pre‐ and post‐SAH administration of minocycline attenuated SAH‐induced vasospasm in rabbits.Interpretation MMP‐9 is a key player in the pathogenesis of DCI. The consistent attenuation of multiple components of DCI with both pre‐ and post‐SAH administration of minocycline across different species and experimental models of SAH, combined with the excellent safety profile of minocycline in humans suggest that a clinical trial in SAH patients is warranted.

NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage

“…Middle cerebral artery diameter was measured as previously reported [ 29 , 30 ]. Five or seven days post-SAH, mice were deeply anesthetized with ketamine and xylazine before being serially perfused through the left ventricle with PBS (5mL), 4% paraformaldehyde (15mL), and 20% Indian ink dissolved in 5% gelatin.…”

Cerebroprotection by dioscin after experimental subarachnoid haemorrhage via inhibiting NLRP3 inflammasome through SIRT1‐dependent pathway

“…Subarachnoid haemorrhage is a medical emergency and causes high morbidity and mortality for individuals worldwide (Macdonald & Schweizer, 2017). Multiple pathophysiological processes occurring after subarachnoid haemorrhage contribute to the poor outcome, which can broadly be categorized into early brain injury and delayed cerebral ischaemia (Fan et al, 2017; Fernandez et al, 2018; Vellimana et al, 2017). Early brain injury is characterized by neuroinflammation, oxidative stress, cerebral oedema and neuronal cell death.…”

Increased level of LIGHT/TNFSF14 is associated with survival in aneurysmal subarachnoid hemorrhage

“…Secondly, the upregulation of the DcR3 may be significant in SAH due to its proinflammatory actions 30 . Its neutralizing effect on LIGHT/TNFSF14 31 may contribute to the detrimental outcome after aSAH.…”