Introduction: Intracerebral hemorrhage (ICH) produces high acute mortality and poor long-term neurological outcomes. Hematoma volume clinically correlates with neurological deterioration; however, no efficacious treatment options exist to improve patient outcomes. Remote limb Ischemic Post-Conditioning (RIC) is the simple, inexpensive, and safe use of repetitive inflation of a blood pressure cuff on a limb to protect distant organs after injury. Ischemic conditioning was efficacious in randomized clinical trials in myocardial infarction, was well tolerated in subarachnoid hemorrhage patients, and showed safety and efficacy, including increased CBF, in a small cohort of patients with intracranial stenosis. Herein, we tested the hypothesis that RIC would improve outcomes after experimental ICH.
Methods: ICH was induced in by the injection of type IV bacterial collagenase into the striatum of adult male CD-1 mice. This procedure induces spontaneous vascular rupture and produces the reproducible formation of an intracerebral hematoma. Mice were randomized for either sham conditioning or once daily RIC beginning 2h after sham/ICH injury and continuing daily thereafter. Hematoma volume and cerebral blood flow were assessed by magnetic resonance imaging (MRI) and by laser speckle imaging, respectively. Flow cytometry was used to determine macrophage activation whereas histological measures were incorporated for quantification of white matter injury.
Results: Once daily RIC accelerated spontaneous hematoma resolution and improved blood flow in the peri-hematoma brain tissue. RIC also reduced cell death and limited long-term white matter injury after ICH. Parabiosis revealed that RIC promoted neurovascular improvement via a blood-derived factor(s). Along these lines, depletion of macrophages using clodronate eliminated the protective effect of RIC. Similarly, RIC increased the macrophage polarization toward the anti-inflammatory M2 phenotype and increased myeloid expression of CD36, a type B scavenger receptor implicated in hematoma resolution.
Conclusions: RIC may non-invasively accelerate spontaneous hematoma resolution via an immune mediated mechanism.
Patient Care: It is hoped that this research will provide a novel treatment for patients with ICH.
Learning Objectives: 1. To demonstrate a beneficial role for non-invasive RIC therapy in accelerating spontaneous hematoma resolution after ICH.
2. To implicate the innate immune system in mediating the protective effects of RIC after ICH.
3. To identify a non-invasive means to modulate macrophage activation.
References: 1. Botker, H.E., et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375, 727-734 (2010).
2. Koch, S. & Gonzalez, N. Preconditioning the human brain: proving the principle in subarachnoid hemorrhage. Stroke 44, 1748-1753 (2013).
3. Hahn, C.D., Manlhiot, C., Schmidt, M.R., Nielsen, T.T. & Redington, A.N. Remote ischemic per-conditioning: a novel therapy for acute stroke? Stroke; a journal of cerebral circulation 42, 2960-2962 (2011).