Antagonists of the Vasopressin V1 Receptor and of the β(1)-Adrenoceptor Inhibit Cytotoxic Brain Edema in Stroke by Effects on Astrocytes - but the Mechanisms Differ (original) (raw)
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The role of vasopressin V1A receptors in cytotoxic brain edema formation following brain injury
Acta Neurochirurgica, 2013
Background The hormone and neuropeptide argininevasopressin is designated to the maintenance of osmotic homoeostasis and blood pressure regulation. While experimental data show vasopressin V 1A receptors to regulate aquaporin (AQP)4 water channel dependent brain water movement, the specific role in vasogenic and cytotoxic edema formation remains unclear. The present study was designed to quantify the V 1A receptor mediated regional brain edema formation in two clinically relevant experimental models, brain injury combined with secondary insult and focal ischemia. Methods Male Sprague-Dawley rats were randomly assigned to a continuous infusion of vehicle (1 % DMSO) or the selective non-peptide V 1A antagonist SR49059 (83nM01 mg/kg) starting before controlled cortical impact (CCI) injury plus hypoxia and hypotension (HH, 30 min), or middle cerebral artery (MCA) occlusion (2 h+2 h reperfusion). Results A global analysis of brain water content by the wet/ dry weight method allowed optimizing the SR49059 dosage, and demonstrated the down-regulation of brain AQP4 expression by immunoblotting. Microgravimetrical quantification in 64 one mm 3 samples per animal (n06 per group) from bregma +2.7 to −6.3 mm analysis demonstrated brain edema to be reduced at 4 h by SR49059 treatment in the injured and contralateral cortex following CCI+HH (p0 0.007, p<0.001) and in the infarct area following MCA occlusion (p00.013, p00.002, p00.004). Conclusions Our findings demonstrate that an early cytotoxic brain edema component following brain injury plus secondary insult or focal ischemia results from a vasopressin V 1A receptor mediated response, and occurs most likely through AQP4 up-regulation. The V 1A antagonist SR49059 offers a new avenue in brain edema treatment and prompts further study into the role of vasopressin following brain injury.
Brain Research, 2003
Our previous study demonstrated that pharmacological inhibition of the Na -K -Cl cotransporter isoform 1 (NKCC1) during ischemia and reperfusion attenuated neuronal damage and edema. In this study, we further investigated whether NKCC1 activity contributes to ischemic damage during either ischemia or reperfusion. Immunoblotting revealed that expression of NKCC1 protein was increased following 2-h focal ischemia in cerebral cortex. A sustained up-regulation of NKCC1 in cortex was detected at 4, 8, 12, and 24 h of reperfusion. An increase in the phosphorylated NKCC1 (NKCC1-p) was found at 4 and 8 h of reperfusion. In striatum, a significant increase in NKCC1 expression occurred between 4 and 24 h of reperfusion and no elevation of NKCC1-p signal was observed. Artificial cerebral spinal fluid (aCSF) or 100 mM bumetanide in aCSF were continuously microdialyzed into left cortices either 1 h prior to ischemia plus 2-h ischemia, or only during 24-h reperfusion. Infarction volume was significantly decreased in the pre-ischemic bumetanide-treated group (P,0.05) but not in the post-ischemic treatment group (P.0.05). In addition, pre-ischemic bumetanide treatment reduced the ipsilateral water content increase by 70% (P,0.05). Inhibition of NKCC1 did not attenuate poly (ADP-ribose) polymerase cleavage or the number of TUNEL-labeled apoptotic cells in ischemic brains. These results suggest that inhibition of NKCC1 attenuates cytotoxic edema and necrotic neuronal death during focal ischemia. Activation of NKCC1 activity plays a role in the early stage of ischemic damage.
Acta neurochirurgica. Supplement, 2011
There is mounting evidence suggesting that arginine vasopressin via its V1a receptor interaction is involved in the regulation of the brain water channel, aquaporin-4 (AQP4). The role of AQP4 in brain edema resolution has been thoroughly investigated in knock-out animal studies, which showed that its depletion increases brain water content in models of vasogenic edema. As a result, we tested the hypothesis that the activation of V1a receptor by it selective agonist will decrease brain edema in a mouse intracerebral hemorrhage (ICH) model. ICH was induced by injection of bacterial collagenase into the right basal ganglia in CD1 male mice (weight 30-35 g). The animals were divided into the following groups: sham, ICH+vehicle, and ICH+AVP V1a receptor agonist. Brain edema and neurological outcomes were evaluated at 24 and 72 h post-ICH. We found that collagenase injection increased brain edema and resulted in subsequent neurobehavioral deficits at both time points. Treatment with our a...
Role of vasopressin and its antagonism in stroke related edema
Journal of Neuroscience Research, 2014
Although many approaches have been tried in the attempt to reduce the devastating impact of stroke, tissue plasminogen activator for thromboembolic stroke is the only proved, effective acute stroke treatment to date. Vasopressin, an acute-phase reactant, is released after brain injury and is partially responsible for the subsequent inflammatory response via activation of divergent pathways. Recently there has been increasing interest in vasopressin because it is implicated in inflammation, cerebral edema, increased intracerebral pressure, and cerebral ion and neurotransmitter dysfunctions after cerebral ischemia. Additionally, copeptin, a byproduct of vasopressin production, may serve as a promising independent marker of tissue damage and prognosis after stroke, thereby corroborating the role of vasopressin in acute brain injury. Thus, vasopressin antagonists have a potential role in early stroke intervention, an effect thought to be mediated via interactions with aquaporin receptors, specifically aquaporin-4. Despite some ambiguity, vasopressin V1a receptor antagonism has been consistently associated with attenuated secondary brain injury and edema in experimental stroke models. The role of the vasopressin V2 receptor remains unclear, but perhaps it is involved in a positive feedback loop for vasopressin expression. Despite the encouraging initial findings we report here, future research is required to characterize further the utility of vasopressin antagonists in treatment of stroke. V
Frontiers in Neuroscience
Background and Purpose: The morbidity and early mortality associated with stroke is largely attributable to cerebral edema and elevated intracranial pressure (ICP). Existing pharmacotherapies do not target the underlying pathophysiology and are often ineffective in sustainably lowering ICP, whilst decompressive craniectomy (DC) surgery is life-saving yet with surgical/peri-operative risk and increased morbidity in the elderly. Accordingly, there is an urgent need for therapies that directly target the mechanisms of edema genesis. Neurogenic inflammation, mediated by substance P (SP) binding to the tachykinin NK1 receptor (NK1-r), is associated with blood-brain barrier (BBB) disruption, cerebral edema and poor outcome post-stroke. NK1-r antagonist treatment ameliorates BBB dysfunction and cerebral edema in rodent stroke models. However, treatment has not been investigated in a large animal model, an important step toward clinical translation. Consequently, the current study compared the efficacy of NK1-r antagonist treatment to DC surgery in reducing ICP post-stroke in a clinically relevant ovine model. Methods: Anesthetized female Merino sheep (65 ± 6 kg, 18-24 months) underwent sham surgery (n = 4) or permanent middle cerebral artery occlusion (n = 22). Stroke animals were randomized into one of 5 treatments: 1×NK1 bolus (4 h), 2×NK1 bolus (4 h;9 h), 3×NK1 bolus (4 h;9 h;14 h), DC surgery (performed at 4 h) or saline vehicle. ICP, blood pressure and blood gasses were monitored for 24 h post-stroke. At 24 h post-stroke anesthetized animals underwent MRI followed by perfusion and brains removed and processed for histological assessment. Results: 2×NK1, 3×NK1 administration or DC surgery significantly (p < 0.05) reduced ICP compared to vehicle. 1×NK1 was ineffective in sustainably lowering ICP. On MRI,
Journal of Cerebral Blood Flow and Metabolism, 2005
Brain edema formation is one of the most important mechanisms responsible for brain damage after ischemic stroke. Despite considerable efforts, no specific therapy is available yet. Arginine vasopressin (AVP) regulates cerebral water homeostasis and has been involved in brain edema formation. In the current study, we investigated the role of AVP V 1 and V 2 receptors on brain damage, brain edema formation, and functional outcome after transient focal cerebral ischemia, a condition comparable with that of stroke patients undergoing thrombolysis. C57/BL6 mice were subjected to 60-min middle cerebral artery occlusion (MCAO) followed by 23 h of reperfusion. Five minutes after MCAO, 100 or 500 ng of [deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-vasopressin (AVP V 1 receptor antagonist) or [adamantaneacetyl(1), O-Et-D-Tyr(2), Val(4), Abu(6), Arg(8,9)]-vasopressin (AVP V 2 receptor antagonist) were injected into the left ventricle. Inhibition of AVP V 1 receptors reduced infarct volume in a dose-dependent manner by 54% and 70% (to 29713 and 19710 mm 3 versus 637 17 mm 3 in controls; Po0.001), brain edema formation by 67% (to 80.4%71.0% versus 82.7%71.2% in controls; Po0.001), blood-brain barrier disruption by 75% (Po0.001), and functional deficits 24 h after ischemia, while V 2 receptor inhibition had no effect. The current findings indicate that AVP V 1 but not V 2 receptors are involved in the pathophysiology of secondary brain damage after focal cerebral ischemia. Although further studies are needed to clarify the mechanisms of neuroprotection, AVP V 1 receptors seem to be promising targets for the treatment of ischemic stroke.
BMC Neurology, 2014
Background: Elevated intracranial pressure from cerebral edema is the major cause of early mortality in acute stroke. Current treatment strategies to limit cerebral edema are not particularly effective. Some novel anti-edema measures have shown promising early findings in experimental stroke models. Vasopressin antagonism in stroke is one such target which has shown some encouraging preliminary results. The aim of this report is to highlight the potential use of vasopressin antagonism to limit cerebral edema in patients after acute stroke. Case presentation: A 57-year-old Caucasian man with new onset diplopia was diagnosed with vertebral artery aneurysm extending into the basilar circulation. He underwent successful elective vertebral artery angioplasty and coiling of the aneurysm. In the immediate post-operative period there was a decline in his neurological status and brain imaging revealed new midbrain and thalamic hemorrhage with surrounding significant brain edema. Treatment with conventional anti-edema therapy was initiated with no significant clinical response after which conivaptan; a mixed vasopressin antagonist was started. Clinical and radiological evaluation following drug administration showed rapid clinical improvement without identification of significant adverse effects.
Journal of Cerebral Blood Flow & Metabolism, 2005
Brain edema formation is one of the most important mechanisms responsible for brain damage after ischemic stroke. Despite considerable efforts, no specific therapy is available yet. Arginine vasopressin (AVP) regulates cerebral water homeostasis and has been involved in brain edema formation. In the current study, we investigated the role of AVP V1 and V2 receptors on brain damage, brain edema formation, and functional outcome after transient focal cerebral ischemia, a condition comparable with that of stroke patients undergoing thrombolysis. C57/BL6 mice were subjected to 60-min middle cerebral artery occlusion (MCAO) followed by 23 h of reperfusion. Five minutes after MCAO, 100 or 500 ng of [deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-vasopressin (AVP V1 receptor antagonist) or [adamantaneacetyl(1), O-Et-D-Tyr(2), Val(4), Abu(6), Arg(8,9)]-vasopressin (AVP V2 receptor antagonist) were injected into the left ventricle. Inhibition of AVP V1 receptors reduced infarct volume in a dose-dependent manner by 54% and 70% (to 29+/-13 and 19+/-10 mm3 versus 63+/-17 mm3 in controls; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), brain edema formation by 67% (to 80.4%+/-1.0% versus 82.7%+/-1.2% in controls; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), blood-brain barrier disruption by 75% (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), and functional deficits 24 h after ischemia, while V2 receptor inhibition had no effect. The current findings indicate that AVP V1 but not V2 receptors are involved in the pathophysiology of secondary brain damage after focal cerebral ischemia. Although further studies are needed to clarify the mechanisms of neuroprotection, AVP V1 receptors seem to be promising targets for the treatment of ischemic stroke.