Hyperbaric oxygen preconditioning attenuates hyperglycemia enhanced hemorrhagic transformation after transient MCAO in rats

<p>Abstract</p> <p>Background</p> <p>Hemorrhagic transformation (HT) can be a devastating complication of ischemic stroke. Hyperbaric oxygen preconditioning (HBO-PC) has been shown to improve blood-brain barrier (BBB) permeability in stroke models. The purpose of this study is to examine whether HBO-PC attenuates HT after focal cerebral ischemia, and to investigate whether the mechanism of HBO-PC against HT includes up-regulation of antioxidants in hyperglycemic rats.</p> <p>Methods</p> <p>Male Sprague-Dawley rats (280-320 g) were divided into the following groups: sham, middle cerebral artery occlusion (MCAO) for 2 h, and MCAO treated with HBO-PC. HBO-PC was conducted giving 100% oxygen at 2.5 atm absolute (ATA), for 1 h at every 24 h interval for 5 days. At 24 h after the last session of HBO-PC, rats received an injection of 50% glucose (6 ml/kg intraperitoneally) and were subjected to MCAO 15 min later. At 24 h after MCAO, neurological behavior tests, infarct volume, blood-brain barrier permeability, and hemoglobin content were measured to evaluate the effect of HBO-PC. Western blot analysis of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was evaluated at multiple time-points before and after MCAO.</p> <p>Results</p> <p>HBO-PC improved neurological behavior test, and reduced infarction volume, HT and Evans blue extravasation in the ipsilateral hemisphere at 24 h after MCAO. Western blot analysis failed to demonstrate up-regulation of Nrf2 in HBO-PC group before and after MCAO. Paradoxically, HBO-PC decreased HO-1 expression at 24 h after MCAO, as compared with htMCAO group.</p> <p>Conclusions</p> <p>HBO-PC improved neurological deficits, infarction volume, BBB disruption, and HT after focal cerebral ischemia. However, its mechanism against focal cerebral ischemia and HT may not include activation of Nrf2 and subsequent HO-1 expression.</p

Hydrocephalus after Subarachnoid Hemorrhage: Pathophysiology, Diagnosis, and Treatment

Hydrocephalus (HCP) is a common complication in patients with subarachnoid hemorrhage. In this review, we summarize the advanced research on HCP and discuss the understanding of the molecular originators of HCP and the development of diagnoses and remedies of HCP after SAH. It has been reported that inflammation, apoptosis, autophagy, and oxidative stress are the important causes of HCP, and well-known molecules including transforming growth factor, matrix metalloproteinases, and iron terminally lead to fibrosis and blockage of HCP. Potential medicines for HCP are still in preclinical status, and surgery is the most prevalent and efficient therapy, despite respective risks of different surgical methods, including lamina terminalis fenestration, ventricle-peritoneal shunting, and lumbar-peritoneal shunting. HCP remains an ailment that cannot be ignored and even with various solutions the medical community is still trying to understand and settle why and how it develops and accordingly improve the prognosis of these patients with HCP

Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice

OBJECTIVE: Hydrogen inhalation was neuroprotective in several brain injury models. Its mechanisms are believed to be related to antioxidative stress. We investigated the potential neurovascular protective effect of hydrogen inhalation especially effect on mast cell activation in a mouse model of intracerebral hemorrhage. DESIGN: Controlled in vivo laboratory study. SETTING: Animal research laboratory. SUBJECTS: One hundred seventy-one 8-week-old male CD-1 mice were used. INTERVENTIONS: Collagenase-induced intracerebral hemorrhage model in 8-week-old male CD-1 mice was used. Hydrogen was administrated via spontaneous inhalation. The blood-brain barrier permeability and neurologic deficits were investigated at 24 and 72 hours after intracerebral hemorrhage. Mast cell activation was evaluated by Western blot and immuno-staining. The effects of hydrogen inhalation on mast cell activation were confirmed in an autologous blood injection model intracerebral hemorrhage. MEASUREMENT AND MAIN RESULTS: At 24 and 72 hours post intracerebral hemorrhage, animals showed blood-brain barrier disruption, brain edema, and neurologic deficits, accompanied with phosphorylation of Lyn kinase and release of tryptase, indicating mast cell activation. Hydrogen treatment diminished phosphorylation of Lyn kinase and release of tryptase, decreased accumulation and degranulation of mast cells, attenuated blood-brain barrier disruption, and improved neurobehavioral function. CONCLUSION: Activation of mast cells following intracerebral hemorrhage contributed to increase of blood-brain barrier permeability and brain edema. Hydrogen inhalation preserved blood-brain barrier disruption by prevention of mast cell activation after intracerebral hemorrhage

PAR-1 antagonist SCH79797 ameliorates apoptosis following surgical brain injury through inhibition of ASK1-JNK in rats

Neurosurgical procedures inevitably produce intraoperative hemorrhage. The subsequent entry of blood into the brain parenchyma results in the release of large amounts of thrombin, a known contributor to perihematomal edema formation and apoptosis after brain injury. The present study seeks to test 1) the effect of surgically induced brain injury (SBI) on thrombin activity, expression of thrombin\u27s receptor PAR-1, and PAR-1 mediated apoptosis; 2) the effect of thrombin inhibition by argatroban and PAR-1 inhibition by SCH79797 on the development of secondary brain injury in the SBI model on rats. A total of 88 Sprague-Dawley male rats were randomly divided into sham, vehicle-, argatroban-, or SCH79797-treated groups. SBI involved partial resection of the right frontal lobe under inhalation isoflurane anesthesia. Sham-operated animals received only craniotomy. Thrombin activity, brain water content, and neurological deficits were measured at 24 h following SBI. Involvement of the Ask1/JNK pathway in PAR-1-induced post-SBI apoptosis was characterized by using Ask1 or JNK inhibitors. We observed that SBI increased thrombin activity, yet failed to demonstrate any effect on PAR-1 expression. Argatroban and SCH79797 reduced SBI-induced brain edema and neurological deficits in a dose-dependent manner. SBI-induced apoptosis seemed mediated by the PAR-1/Ask1/JNK pathways. Administration of SCH79797 ameliorated the apoptosis following SBI. Our findings indicate that PAR-1 antagonist protects against secondary brain injury after SBI by decreasing both brain edema and apoptosis by inactivating PAR-1/Ask1/JNK pathway. The anti-apoptotic effect of PAR-1 antagonists may provide a promising path for therapy following SBI

Vascular adhesion protein-1 inhibition provides antiinflammatory protection after an intracerebral hemorrhagic stroke in mice

The systemic immune response has a vital role in propagating the damage of an intracerebral hemorrhage (ICH). Vascular adhesion protein-1 (VAP-1), a semicarbazide (SCZ)-sensitive-amine-oxidase, was found in previous studies to have a role in migration of immune cells. In this study, we hypothesize that VAP-1 inhibition may decrease brain injury by attenuating the transmigration of immune cells to the injury site, and by doing so, reduce cerebral edema and improve neurobehavioral function in mice. Two VAP-1 inhibitors, LJP1586 and SCZ were given 1 hour after ICH induction by either collagenase or autologous blood injection. The VAP-1 siRNA, a VAP-1 gene silencer, and human recombinant AOC3 protein, a VAP-1 analogue, were delivered by intracerebroventricular injection. Postassessment included neurobehavioral testing, brain edema measurement, quantification of neutrophil infiltration and microglia/macrophage activation, and measurement of intercellular adhesion molecule-1 (ICAM-1), P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) expression 24 hours after ICH. We found that LJP1586 and SCZ reduced brain edema and neurobehavioral deficits 24 hours after ICH induction. These two drugs were also found to decrease levels of ICAM-1, MCP-1, TNF-α, and inhibit neutrophilic infiltration and microglia/macrophage activation. We conclude that VAP-1 inhibition provided antiinflammation effect by reducing adhesion molecule expression and immune cell infiltration after ICH

Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage

The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects

The roles of astrocyte in the brain pathologies following ischemic stroke

: In this work, we systematically explored the physiological functions of astrocytes and their roles following ischemic stroke, additionally, the potential therapy strategy targeting the astrocytes was also discussed. : This work searched the PubMed database (including MEDLINE) until 14 Feb 2018, and furthermore, the studies were identified through cross-referencing and by consulting the experts in this field. : This study indicated that the astrocytes can not only play harmful roles following ischemic stroke through release of inflammatory factors and formation of glial scar but also have protective effects through quenching glutamate excitotoxicity and maintaining the clearance function of glymphatic system in brain. : Owing to their important roles in physiological functions of brain and in the pathological conditions following ischemic stroke, the astrocytes might be a potential but promising therapeutic target for treating the ischemic stroke in the future