Prevention of hypoxic brain oedema by the administration of vasopressin receptor antagonist OPC-31260.
ABSTRACT The numerous situations which can result in cerebral hypoxic damage occur in newborn infants and in the elderly. In research aimed at more effective therapeutic intervention in ischaemic disorders of the brain, the animal model used and the principles of the causal therapy should be better outlined. The effects of the non-peptide AVPR (V2) antagonist 5-dimethylamino-1-[4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by general cerebral hypoxia were studied in rats. The general cerebral hypoxia was produced by bilateral common carotid ligation in Sprague-Dawley rats of the CFY strain. By 6h after the ligation, half of the rats had died, but the survival rate was significantly higher following OPC-31260 administration. Electron microscopic examinations revealed typical ischaemic changes after the carotid ligation, and OPC-31260 treatment did not significantly reduce the hypoxic signs in the brain cortex; only a certain decrease in the pericapillary oedema was observed. The carotid ligation increased the brain contents of water and Na(+) and enhanced the plasma AVP level. The increased brain water and Na(+) accumulation was prevented by OPC-31260 administration, but the plasma AVP level was further enhanced by OPC-31260. These results demonstrate the important role of AVP in the development of the disturbances in brain water and electrolyte balance in response to general cerebral hypoxia. The carotid ligation-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on the renal AVPR (V2). These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.
- SourceAvailable from: Eduardo Candelario-Jalil
Chapter: Brain Edema in Neurological Diseases[Show abstract] [Hide abstract]
ABSTRACT: In the brain, the transport of water and solute is precisely regulated. This maintains a stable and unique microenvironment that is critical to brain function. Cerebral edema results from the excess of fluid in the brain’s intra- and extracellular spaces. This occurs in response to a wide variety of insults, including cerebral ischemia, hypoxia, infection, brain tumors, and neuroinflammation. Cytotoxic edema leads to intracellular swelling without alterations in vascular permeability. Vasogenic edema is associated with damage to the blood–brain barrier. These types of edema rarely exist in isolation. In most neuropathological conditions, one type of edema predominates, but both coexist. This chapter focuses on the major molecular mechanisms triggering brain edema, including alterations in ion channels and transporters, matrix metalloproteinases, tight junction protein degradation, free radicals, and products of the arachidonic acid metabolism. We review present knowledge of the contribution to brain edema of molecules such as aquaporins, vasopressin, vascular endothelial growth factor, angiopoietins, and bradykinin. We further examine brain imaging modalities that have revolutionized clinical diagnosis of cerebral edema. Finally, we provide a critical evaluation of the current strategies for the treatment of brain edema. KeywordsVasogenic edema-Neurovascular unit-Matrix metalloproteinases-Aquaporins-Blood–brain barrier-Imaging01/2010: pages 125-168;
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ABSTRACT: Background We ascertained the occurrence of global cerebral edema manifesting as increased brain volume in subjects with intracerebral hemorrhage (ICH) and explored the relationship between subject characteristics and three month outcomes. Methods A post-hoc analysis of a multicenter prospective study that recruited patients with ICH, elevated SBP ≥170 mm Hg, and Glasgow Coma Scale (GCS) score ≥8, who presented within 6 h of symptom onset was performed. Computed tomographic (CT) scans at baseline and 24 h, submitted to a core image laboratory, were analyzed to measure total brain, hematoma, and perihematoma edema volumes from baseline and 24-h CT scans using image analysis software. The increased brain volume was determined by subtracting the hematoma and perihematomal edema volumes from the total brain volume. Results A total of 18 (44 %) of 41 subjects had increased brain volume that developed between initial CT scan and 24-h CT scan. The median increase in brain volume among the 18 subjects was 35 cc ranging from 0.12 to 296 cc. The median baseline GCS score was 15 in both groups of subjects who experienced increased brain volume and those who did not, and the median hematoma volume was 10.18 and 6.73, respectively. Three of the 18 subjects with increased brain volume underwent concurrent neurological deterioration and one subject died during hospitalization. Conclusions We found preliminary evidence of increased cerebral brain volume in subjects with good grade and small ICHs, which may be suggestive of global cerebral edema.Neurocritical Care 06/2013; · 3.04 Impact Factor
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ABSTRACT: Cerebral edema is a devastating consequence of brain injury leading to cerebral blood flow compromise and worsening parenchyma damage. In the present study, we investigated the effects of arginine-vasopressin (AVP) V(1a) receptor inhibition following an intracerebral hemorrhagic (ICH) brain injury in mice and closely assessed the role it played in cerebral edema formation, neurobehavioral functioning, and blood-brain-barrier (BBB) disruption. To support our investigation, SR49059, an AVP V(1a) receptor competitive antagonist, and NC1900, an arginine-vasopressin analogue, were used. Male CD1 mice (n=205) were randomly assigned to the following groups: naïve, sham, ICH, ICH with SR49059 at 0.5 mg/kg, ICH with SR49059 at 2mg/kg, ICH with NC1900 at 1 ng/kg, ICH with NC1900 at 10 ng/kg, and ICH with a combination of SR49059 at 2 mg/kg and NC1900 at 10 ng/kg. ICH was induced by using the collagenase injection model and treatment was given 1h after surgery. Post assessment was conducted at 6, 12, 24, and 72 h after surgery and included brain water content, neurobehavioral testing, Evans Blue assay, western blotting, and hemoglobin assay. The study found that inhibition of the AVP V(1a) receptor significantly reduced cerebral edema at 24 and 72 h post-ICH injury and improved neurobehavioral function while reducing BBB disruption at 72 h. Western blot analysis demonstrated increased protein expression of aquaporin 4 (AQP4) in vehicle, which was reduced with AVP V(1a) receptor inhibition. Our study suggests that blockage of the AVP V(1a) receptor, is a promising treatment target for improving ICH-induced brain injury. Further studies will be needed to confirm this relationship and determine future clinical direction.Neurochemistry International 01/2011; 58(4):542-8. · 2.66 Impact Factor