Neuroprotection afforded by antagonists of endothelin-1 receptors in experimental stroke

Moldes, Octavio; Sobrino, Tomás; Blanco, Miguel; Agulla, Jesús; Barral, David; Ramos‐Cabrer, Pedro; Castillo, José

doi:10.1016/j.neuropharm.2012.08.019

Cited by 23 publications

(18 citation statements)

References 36 publications

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“…In humans, ET-1 levels >5.5 fmol/mL in serum are linked to severe brain edema in acute stroke patients (35). ET-1 A plays a protective role during brain edema (36), but ET-1 B receptors also regulate astrocytic function (31); in an experimental rat model of stroke, an ET-1 B antagonist could reduce brain edema, serum ET-1, and astrocyte swelling (37). Recently, ET-1 has been shown to promote NO production and astrocyte migration by activation of ET-1 B and NF-κB, inducing iNOS (38).…”

Section: Discussionmentioning

confidence: 99%

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

Chen

Yang

Kong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca 2+, and PKCe; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1+ and AQP4 + , we show that transfected CRFR1+ contributes to edema via transfected AQP4 + . In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema.water permeability | high altitude | acute mountain sickness A pproximately 140 million people around the world live at altitudes of >2,500 m, including >8 million who live on the Qinghai-Tibet plateau of China at an average elevation of >4,000 m. Living at these altitudes requires physiological adaptations to compensate for the lower partial pressure of oxygen (1). In travelers who ascend to altitudes too high or too quickly (2-4) or in people with fatigue and infection or psychological stress (3, 4), hypoxia can induce acute mountain sickness (AMS) that can develop into high-altitude cerebral edema (HACE), a serious and often fatal condition (2-6). Today's ability to travel rapidly to high altitudes means that, every year, millions of people are exposed to the risk of AMS and HACE (7).In human volunteers exposed for 32 h to hypobaric hypoxia (corresponding to 4,572 m altitude), brain volume increases by 2.77% (8), whereas normobaric hypoxia (12% O 2 , corresponding to a simulated altitude of 4,500 m) for 16 h produces 50% AMS, headache, a mild increase in brain volume, and cytotoxic cerebral edema (9). A recent study reported that seven of nine male students exposed to isobaric hypoxia (inhaled room air enriched with N 2 for 6 h to obtain arterial saturation values of 75-80%) developed AMS; the mean apparent diffusion coefficient (ADC) increased by 2.12% in these subjects, indicating mild extracellular (vasogenic) cerebral edema. The ADC changes were negatively correlated with AMS scores, suggesting that severe AMS is associated with intracellular (cytotoxic) cerebral edema in addition to vasogenic edema (10).In parallel with the increasing brain water content, hypoxia acutely activates the hypothalamic-pituitary-adrenal axis in rats (11-13), increasing corticotropin-releasing factor (CRF) and endothelin-1 (ET-1)...

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Section: Discussionmentioning

confidence: 99%

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

Chen

Yang

Kong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The model of collagenase‐induced hemorrhage primarily damages the striatum, producing a small forelimb paresis contralateral to the lesion. Sensorimotor deficits after ischemic insult were assessed using the cylinder test, as previously described 23. This test evaluates limb asymmetry during the exploratory activity.…”

Section: Methodsmentioning

confidence: 99%

“…Sensorimotor deficits after ischemic insult were assessed using the cylinder test, as previously described. 23 This test evaluates limb asymmetry during the exploratory activity. Each animal was put in a cylinder with a 20-cm-diameter transparent base.…”

Section: Behavioral Testsmentioning

confidence: 99%

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Rodríguez

Sobrino

López-Arias

et al. 2017

JAHA

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BackgroundIntracerebral hemorrhage (ICH) is an acute neurological disorder with high mortality and no effective treatment. In addition to the initial bleeding event, rebleeding and hematoma expansion are associated with poor outcome in these patients. We studied the effectiveness of the new antifibrinolytic agent CM352, a short‐half‐life matrix metalloproteinase inhibitor, for achieving early hemostasis and improving functional recovery in a rat model of collagenase‐induced ICH.Methods and Results ICH was induced by striatal injection of collagenase, and 1 hour later, rats received an intravenous injection of saline (n=6) or CM352 (1 mg/kg, n=6). Hematoma (basal and after 3 and 24 hours) and lesion (14 days) volumes were quantified on T2‐weighted (T2) magnetic resonance images. Neurological and functional recovery was evaluated by using Bederson score and a cylinder test (basal, 24 hours, and 14 days). Early treatment (1 hour) with CM352 was efficient reducing hematoma expansion at 3 hours (P<0.01) and, more markedly, at 24 hours (P<0.01). Decreased bleeding after antifibrinolytic treatment was accompanied by reduced interleukin‐6 levels at 3 hours (P<0.05) and smaller lesion volume at 14 days (P<0.01). CM352 drastically reduced sensorimotor impairment (cylinder test) after ICH in rats at 24 hours (P<0.01) and 14 days (P<0.01). Similarly, it also attenuated neurological deficit (Bederson scale) at 24 hours (P<0.01) and 14 days (P<0.01). Interestingly, late (3 hours) CM352 administration also resulted in reduced lesion size and better functional outcome.Conclusions CM352, a new antifibrinolytic agent and matrix metalloproteinase inhibitor, effectively prevented hematoma growth and reduced lesion size in ICH in association with improved functional and neurological recovery.

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“…Endothelin receptor antagonists including ambrisentan are noted to exert their anti-inflammatory actions along with reduction in reactive oxygen species (ROS) generation which are subsequently responsible for endothelial dysfunction [18,19]. ET receptor antagonists have also been shown to provide a beneficial effect in various cerebrovascular disorders such as moyamoya disease [20], ischemic stroke [21] and subarachnoid hemorrhage [22]. Furthermore it has been recently reported that these antagonists have potential for the treatment of AD [23].…”

Section: Introductionmentioning

confidence: 99%

Ameliorative Effect of a Selective Endothelin ET_AReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

Mangat

Jaggi

Singh

2014

Korean J Physiol Pharmacol

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The present study was designed to investigate the efficacy of selective ETA receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5th to 8th week of L-methionine treatment). On 52nd day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective ETA receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.

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Neuroprotection afforded by antagonists of endothelin-1 receptors in experimental stroke

Cited by 23 publications

References 36 publications

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Ameliorative Effect of a Selective Endothelin ET_AReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

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Neuroprotection afforded by antagonists of endothelin-1 receptors in experimental stroke

Cited by 23 publications

References 36 publications

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Ameliorative Effect of a Selective Endothelin ETAReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

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Ameliorative Effect of a Selective Endothelin ET_AReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia