Effect of small molecule vasopressin V1a and V2 receptor antagonists on brain edema formation and secondary brain damage following traumatic brain injury in mice.

The attenuation of brain edema is a major therapeutic target after traumatic brain injury (TBI). Vasopressin (AVP) is well known to play a major role in the regulation of brain water content and vasoendothelial functions and to be involved in brain edema formation. Therefore, the aim of the current study was to analyze the antiedematous efficacy of a clinically relevant, nonpeptidic AVP V1a and V2 receptor antagonists.

Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients.

Background: In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10-12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies.

Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles.

Rationale: Stroke is the third most common cause of death in industrialized countries. The main therapeutic target is the ischemic penumbra, potentially salvageable brain tissue that dies within the first few hours after blood flow cessation. Hence, strategies to keep the penumbra alive until reperfusion occurs are needed.

Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study.

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a severe, cerebral perfusion pressure (CPP)-independent reduction in cerebral blood flow suggesting alterations on the level of cerebral microvessels. Therefore, we aimed to use in-vivo imaging to investigate the cerebral microcirculation after experimental SAH. Subarachnoid hemorrhage was induced in C57/BL6 mice by endovascular perforation.

Vasopressin V(1a) receptors mediate posthemorrhagic systemic hypertension thereby determining rebleeding rate and outcome after experimental subarachnoid hemorrhage.

Background And Purpose: Arginine vasopressin V(1) receptors have been suggested to be involved in the pathophysiology of acute brain injury. Therefore, we aimed to determine the role of arginine vasopressin V(1) receptors after experimental subarachnoid hemorrhage (SAH).

Methods: Sprague-Dawley rats subjected to SAH by endovascular puncture received either vehicle or a V(1) receptor antagonist intravenously from 1 minute before until 3 hours after SAH.

Role of apoptosis inducing factor (AIF) for hippocampal neuronal cell death following global cerebral ischemia in mice.

The molecular mechanisms of neuronal cell death following circulatory arrest are still not fully understood. In the current study we investigated the role of apoptosis-inducing factor (AIF), a major caspase-independent mitochondrial cell death protein, for neuronal cell death following global cerebral ischemia (GCI). C57/Bl6 or low AIF expressing Harlequin mutant mice (AIF(low)) and their wild-type littermates were subjected to 10 min of GCI.

Contribution of bradykinin receptors to the development of secondary brain damage after experimental subarachnoid hemorrhage.

Background: Subarachnoid hemorrhage (SAH) is the stroke subtype with the highest mortality and morbidity. Which molecular events mediate brain damage after SAH is not well understood.

Objective: To investigate the role of proinflammatory bradykinin B(1) and B(2) receptors for the pathophysiology of SAH.

Characterization of a 3-vessel occlusion model for the induction of complete global cerebral ischemia in mice.

Existing murine models of global cerebral ischemia are technically challenging thereby hampering the use of genetically engineered mice to study cardiac arrest-induced brain damage. We therefore investigated, if disconnecting the cerebral circulation from vertebral collateral blood flow by proximal occlusion of the basilar artery together with temporary bilateral common carotid artery occlusion (BCCAo) may be a more feasible approach. C57/Bl6 mice were anesthetized and the basilar artery was occluded through a ventral approach.

Standardized induction of subarachnoid hemorrhage in mice by intracranial pressure monitoring.

Background And Purpose: Subarachnoid hemorrhage (SAH) is the subtype of stroke with the most unfavorable outcome but the least well investigated molecular pathophysiology. Among others, not sufficiently well standardized in vivo models suitable for the use with transgenic animals may be responsible for this situation. Therefore the aim of the current study was to detect suitable intra-operative parameters for the controlled and standardized induction of SAH in mice and to characterize the long-term functional and histopathological outcome of mice subjected to this procedure.

Temporal profile of thrombogenesis in the cerebral microcirculation after traumatic brain injury in mice.

Traumatic brain injury (TBI) is associated with an almost immediate reduction in cerebral blood flow (CBF). Because cerebral perfusion pressure is often normal under these circumstances it was hypothesized that the reduction of post-traumatic CBF has to occur at the level of the microcirculation. The aim of the current study was to investigate whether cerebral microvessels are involved in the development of blood flow disturbances following experimental TBI.

The role of bradykinin B(1) and B(2) receptors for secondary brain damage after traumatic brain injury in mice.

Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B(1)-, and B(2)-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter.

The novel nitric oxide synthase inhibitor 4-amino-tetrahydro-L-biopterine prevents brain edema formation and intracranial hypertension following traumatic brain injury in mice.

Brain edema formation, resulting in increased intracranial pressure (ICP), is one of the most deleterious consequences of traumatic brain injury (TBI). Nitric oxide (NO) has previously been shown to be involved in the damage of the blood-brain barrier (BBB) and, thus, in the formation of post-traumatic brain edema; however, this knowledge never resulted in a clinically relevant therapeutic option because available NO synthase inhibitors have serious side effects in man. The aim of the current study was to investigate the therapeutic efficacy of VAS203, a novel tetrahydrobiopterine (BH3)-based NOS inhibitor, in experimental TBI.

Inhibition of bradykinin B2 receptors before, not after onset of experimental subarachnoid hemorrhage prevents brain edema formation and improves functional outcome.

Objective: Brain edema following subarachnoid hemorrhage (SAH) is a result of impairment of cerebral autoregulation and breakdown of the blood-brain barrier. We investigated the role of bradykinin B2 receptors (BrdB2Rs) on brain edema formation after SAH.

Design: In vivo and ex vivo animal study.

Anatibant, a selective non-peptide bradykinin B2 receptor antagonist, reduces intracranial hypertension and histopathological damage after experimental traumatic brain injury.

Bradykinin, the main metabolite of the kallikrein-kinin system and one of the first mediators released during inflammation, is well known to increase the permeability of the blood brain barrier (BBB) by activation of kinin B2 receptors and hence promote brain edema formation following traumatic brain injury (TBI). Anatibant (LF 16-0687), a selective non-peptide bradykinin B2 receptor antagonist, reduces brain edema after experimental TBI, however, so far no data are available if Anatibant reduces also the sequels of brain edema formation, i.e.

Brain edema formation and neurological impairment after subarachnoid hemorrhage in rats. Laboratory investigation.

Object: Global cerebral edema is an independent risk factor for early death and poor outcome after subarachnoid hemorrhage (SAH). In the present study, the time course of brain edema formation, neurological deficits, and neuronal cell loss were investigated in the rat filament SAH model.

Methods: Brain water content and neurological deficits were determined in rats randomized to sham (1-, 24-, or 48-hour survival), SAH by endovascular perforation (1-, 24-, or 48-hour survival), or no surgery (control).

Role of vasopressin V(1a) and V2 receptors for the development of secondary brain damage after traumatic brain injury in mice.

Brain edema is still one of the most deleterious sequels of traumatic brain injury (TBI), and its pathophysiology is not sufficiently understood. The goal of the current study was to investigate the role of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), an important regulator of tissue water homeostasis, for the formation of post-traumatic brain edema, intracranial pressure (ICP), brain damage, and functional deficits following brain trauma. C57/B16 mice (n=112) were subjected to controlled cortical impact (CCI; 8m/s, 1 mm).

Expression and functional role of potassium-chloride cotransporters (KCC) in astrocytes and C6 glioma cells.

Brain edema formation following brain injury is a serious but still poorly treatable medical condition. The understanding of volume regulation in astrocytes, the main cells involved in the formation of cytotoxic brain edema, is key for the development of novel treatment strategies. This study investigates the role of potassium-chloride cotransporters (KCC) for cell volume regulation in glial cells.

Role of cortical spreading depressions for secondary brain damage after traumatic brain injury in mice.

In recent years, several studies have unequivocally shown the occurrence of cortical spreading depressions (CSDs) after stroke and traumatic brain injury (TBI) in humans. The fundamental question, however, is whether CSDs cause or result from secondary brain damage. The aim of the current study was, therefore, to investigate the role of CSDs for secondary brain damage in an experimental model of TBI.

Neurological impairment in rats after subarachnoid hemorrhage--a comparison of functional tests.

Functional outcome has become a key parameter for the determination of the efficacy of therapeutic interventions. Unfortunately, functional tests are not established for filament perforation induced subarachnoid hemorrhage (SAH). Therefore, we evaluated generally applied functional tasks for their potential to discriminate between various degrees of neuronal damage.

Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-kappaB transcriptional activity.

Acute and chronic neurodegeneration, for example, following brain injury or Alzheimer's disease, is characterized by programmed death of neuronal cells. The present study addresses the role and interaction of p53- and NF-kappaB-dependent mechanisms in delayed neurodegeneration following traumatic brain injury (TBI). After experimental TBI in mice p53 rapidly accumulated in the injured brain tissue and translocated to the nucleus of damaged neurons, whereas NF-kappaB transcriptional activity simultaneously declined.

Characterization of microvascular basal lamina damage and blood-brain barrier dysfunction following subarachnoid hemorrhage in rats.

Vasogenic brain edema is one of the major determinants for mortality following subarachnoid hemorrhage (SAH). Although the formation of vasogenic brain edema occurs on the microvascular level by opening of endothelial tight junctions and disruption of the basal lamina, microvascular changes following experimental SAH are poorly characterized. The aim of the present study was therefore to investigate the time course of blood-brain barrier (BBB) dysfunction and basal lamina damage following SAH as a basis for the better understanding of the pathophysiology of SAH.

Effect of early and delayed decompressive craniectomy on secondary brain damage after controlled cortical impact in mice.

The timing of decompressive craniectomy for the treatment of increased intracranial pressure (ICP) after traumatic brain injury (TBI) is a widely discussed clinical issue. Although we showed recently that early decompression is beneficial following experimental TBI, it remains unclear to what degree decompression craniectomy reduces secondary brain damage and if craniectomy is still beneficial when it is delayed by several hours as often inevitable during daily clinical practice. The aim of the current study was therefore to investigate the influence of craniectomy on secondary contusion expansion and brain edema formation and to determine the therapeutic window of craniectomy.

Lactacidosis-induced glial cell swelling depends on extracellular Ca2+.

Cerebral tissue acidosis following ischemia or traumatic brain injury contributes to cytotoxic brain edema formation. In vitro lactacidosis induces swelling of glial cells by intracellular Na+- and Cl--accumulation by the Na+/H+-antiporter, Cl-/HCO3--antiporters and the Na+-K+-2Cl--cotransport. The present study aimed to elucidate whether mechanisms of lactacidosis-induced glial swelling are dependent on intra- or extracellular Ca2+-ions.