Inflammation of the choroid plexus and ependymal layer of the ventricle following intraventricular hemorrhage.

Intraventricular hemorrhage (IVH), which afflicts thousands of people of all ages every year, frequently results in the development of communicating hydrocephalus. Classically, IVH-induced hydrocephalus has been attributed to reduced resorption of cerebrospinal fluid (CSF) due to dysfunction of arachnoid granulations, but this explanation may be incomplete. We hypothesized that IVH would cause inflammation of the choroid plexus and of the ependymal lining of the ventricles, resulting in dysfunction of these barrier cells. Barrier dysfunction, in turn, would be expected to cause an increase in production of abnormal protein-rich CSF and transependymal migration of CSF. We tested this hypothesis using a rat model of IVH, in which 160 µl of autologous blood was infused into the lateral ventricle, resulting in a twofold increase in ventricular size 48 h later. In this model, we found significant activation of nuclear factor κB (NF-κB) signaling by the CSF barrier cells of the choroid plexus and ependymal lining. Moreover, these inflammatory changes were associated with abnormal uptake of serum-derived IgG by the barrier cells, a phenomenon closely linked to abnormal permeability of the blood-brain barrier. We conclude that inflammation marked by NF-κB signaling is a prominent feature after IVH and may account for certain pathophysiological sequelae associated with IVH.

Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke.

BACKGROUND AND PURPOSE: Ischemia/hypoxia induces de novo expression of the sulfonylurea receptor 1-regulated NC(Ca-ATP) channel. In rodent models of ischemic stroke, early postevent administration of the sulfonylurea, glibenclamide, is highly effective in reducing edema, mortality, and lesion volume, and in patients with diabetes presenting with ischemic stroke, pre-event plus postevent use of sulfonylureas is associated with better neurological outcome. However, the therapeutic window for treatment with glibenclamide has not been studied. METHODS: We examined the effect of low-dose (nonhypoglycemogenic) glibenclamide in 3 rat models of ischemic stroke, all involving proximal middle cerebral artery occlusion (MCAo): a thromboembolic model, a permanent suture occlusion model, and a temporary suture occlusion model with reperfusion (105 minutes occlusion, 2-day reperfusion). Treatment was started at various times up to 6 hours post-MCAo. Lesion volumes were measured 48 hours post-MCAo using 2,3,5-triphenyltetrazolium chloride. RESULTS: Glibenclamide reduced total lesion volume by 53% in the thromboembolic MCAo model at 6 hours, reduced corrected cortical lesion volume by 51% in the permanent MCAo model at 4 hours, and reduced corrected cortical lesion volume by 41% in the temporary MCAo model at 5.75 hours (P<0.05 for all 3). Analysis of pooled data from the permanent MCAo and temporary MCAo series indicated a sigmoidal relationship between hemispheric swelling and corrected cortical lesion volume with the half-maximum cortical lesion volume being observed with 10% hemispheric swelling. CONCLUSIONS: Low-dose glibenclamide has a strong beneficial effect on lesion volume and has a highly favorable therapeutic window in several models of ischemic stroke.

Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) causes secondary brain injury due to vasospasm and inflammation. Here, we studied a rat model of mild-to-moderate SAH intended to minimize ischemia/hypoxia to examine the role of sulfonylurea receptor 1 (SUR1) in the inflammatory response induced by SAH. mRNA for Abcc8, which encodes SUR1, and SUR1 protein were abundantly upregulated in cortex adjacent to SAH, where tumor-necrosis factor-alpha (TNFalpha) and nuclear factor (NF)kappaB signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNFalpha. To investigate the functional consequences of SUR1 expression after SAH, we studied the effect of the potent, selective SUR1 inhibitor, glibenclamide. We examined barrier permeability (immunoglobulin G, IgG extravasation), and its correlate, the localization of the tight junction protein, zona occludens 1 (ZO-1). SAH caused a large increase in barrier permeability and disrupted the normal junctional localization of ZO-1, with glibenclamide significantly reducing both effects. In addition, SAH caused large increases in markers of inflammation, including TNFalpha and NFkappaB, and markers of cell injury or cell death, including IgG endocytosis and caspase-3 activation, with glibenclamide significantly reducing these effects. We conclude that block of SUR1 by glibenclamide may ameliorate several pathologic effects associated with inflammation that lead to cortical dysfunction after SAH.