Cardiac arrest-induced regional blood–brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain

Abstract

Brief cardiac arrest and survival is often associated with marked neurological alterations related to cognitive and sensory motor functions. However, detail studies using selective vulnerability of brain after cardiac arrest in animal models are still lacking. We examined selective vulnerability of five brain regions in our well-established cardiac arrest model in pigs. Using light and electron microscopic techniques in combinations with immunohistochemistry, we observed that 5, 30, 60 and 180 min after cardiac arrest results in progressive neuronal damage that was most marked in the thalamus followed by cortex, hippocampus, hypothalamus and the brain stem. The neuronal damages are largely evident in the areas showing leakage of serum albumin in the neuropil. Furthermore, a tight correlation was seen between neuronal damage and increase in brain water content and Na(+) indicating vasogenic edema formation after cardiac arrest. Damage to myelinated fibers and loss of myelin as seen using Luxol fast blue and myelin basic protein (MBP) immunoreactivity is clearly evident in the brain areas exhibiting neuronal damage. Upregulation of GFAP positive astrocytes closely corresponds with neuronal damages in different brain areas after cardiac arrest. At the ultrastructural level, perivascular edema together with neuronal, glial and endothelia cell damages is frequent in the brain areas showing albumin leakage. Damage to both pre- and post-synaptic membrane is also common. Treatment with methylene blue, an antioxidant markedly reduced neuronal damage, leakage of albumin, overexpression of GFAP and damage to myelin following cardiac arrest. Taken together, these observations suggest that (a) cardiac arrest is capable to induce selective neuronal, glial and myelin damage in different parts of the pig brain, and (b) antioxidant methylene blue is capable to induce neuroprotection by reducing BBB disruption. These observations strongly suggest that the model could be used to explore new therapeutic agents to enhance neurorepair following cardiac arrest-induced brain damage for therapeutic purposes.

Hydrogen Sulfide Inhalation Decreases Early Blood—Brain Barrier Permeability and Brain Edema Induced by Cardiac Arrest and Resuscitation

“…18,30 We evaluated BBB disruption in the cortex and hippocampus because neuronal injury is most marked in the cortex and hippocampus after CA. 8 In our CA and resuscitation model, we found permeability of the BBB to low (FITC-dextran) and high (EBalbumin) molecular weight markers at 24 hours after ROSC, similar to other studies. 31,32 Inhalation of 80-p.p.m.…”

“…Disruption of the BBB leads to extravasation of serum albumin, other macromolecular proteins, and cellular elements into the brain extracellular space, resulting in vasogenic brain edema, neuronal apoptosis, and cell death. 8,9 Matrix metalloproteinase-9 (MMP-9), 10 vascular endothelial growth factor (VEGF), 11 and angiogenin-1 (Ang-1) 12 play important roles in maintaining the integrity of the BBB. Matrix metalloproteinase-9 promotes BBB damage and brain edema in the early period of cerebral ischemia by degrading the extracellular matrix of cerebral microvessel basal lamina.…”

White Matter Changes in Comatose Survivors of Anoxic Ischemic Encephalopathy and Traumatic Brain Injury: Comparative Diffusion-Tensor Imaging Study

“…Primary axonal damage induces changes in the fluid microenvironment of the central nervous system, to which in turn myelin is susceptible (21)(22)(23)(24). The moderate l ⊥ increases in our cardiac arrest patients are consistent with such secondary myelin damage (25). Conversely, the marked l ⊥ increase in many areas of TBI patients suggests myelin damage, edema, and/or macrophage infiltration as the primary injury.…”

Preventing Ischemic Brain Injury after Sudden Cardiac Arrest Using NO Inhalation

“…Th e mechanisms responsible for post-cardiac arrest brain injury include excitotoxicity, free radical formation, pathological activation of proteases, and cell death signaling [18], [19]. Many of the injurious pathways are executed over hours to days following return of spontaneous circulation (ROSC) [20], [21]. While the protracted time-course of brain injury suggests a broad therapeutic window for neuroprotective strategies follow ing cardiac arrest [19], no pharmacological agents have been proven to be eff ective in improving neurological outcomes in post-cardiac arrest patients.…”