Therapeutic time window for conivaptan treatment against stroke-evoked brain edema and blood-brain barrier disruption in mice

Ischemic stroke is often complicated by brain edema, disruption of blood-brain barrier (BBB), and uncontrolled release of arginine-vasopressin (AVP). Conivaptan, a V1a and V2 receptor antagonist, reduces brain edema and minimizes damage to the blood-brain barrier after stroke. Most stroke patients d...

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Published in:PloS one 2017-08, Vol.12 (8), p.e0183985-e0183985
Main Authors: Zeynalov, Emil, Jones, Susan M, Elliott, J Paul
Format: Article
Language:English
Subjects:
Animals
Antidiuretic Hormone Receptor Antagonists - therapeutic use
Arginine
Argipressin
Argipressin receptors
Benzazepines - therapeutic use
Biology and Life Sciences
Blood-brain barrier
Blood-Brain Barrier - drug effects
Blood-Brain Barrier - pathology
Brain damage
Brain Edema - drug therapy
Brain Edema - etiology
Brain Edema - pathology
Brain injury
Brain research
Cerebral blood flow
Cerebral edema
Complications and side effects
Conivaptan hydrochloride
Critical care
Disruption
Dosage and administration
Drug dosages
Drug therapy
Edema
Experiments
Health aspects
Infarction, Middle Cerebral Artery - complications
Infarction, Middle Cerebral Artery - pathology
Ischemia
Laboratories
Male
Medical research
Medicine and Health Sciences
Metabolism
Mice
Mice, Inbred C57BL
Neurological diseases
Occlusion
Patient outcomes
Physiology
Reperfusion
Risk factors
Rodents
Stroke
Surgery
Therapy
Traumatic brain injury
Vasopressin
Veins & arteries
Windows (intervals)
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Jones, Susan M
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description Ischemic stroke is often complicated by brain edema, disruption of blood-brain barrier (BBB), and uncontrolled release of arginine-vasopressin (AVP). Conivaptan, a V1a and V2 receptor antagonist, reduces brain edema and minimizes damage to the blood-brain barrier after stroke. Most stroke patients do not receive treatment immediately after the onset of brain ischemia. Delays in therapy initiation may worsen stroke outcomes. Therefore, we designed a translational study to explore the therapeutic time window for conivaptan administration. Mice were treated with conivaptan beginning 3, 5, or 20 hours after 60-minute focal middle cerebral artery occlusion. Treatments were administered by continuous IV infusion for a total of 48 hours. Brain edema and blood-brain barrier (BBB) disruption were evaluated at endpoint. Conivaptan therapy initiated at 3 hours following ischemia reduced edema in the ipsilateral hemisphere, which corresponded with improvements in neurological deficits. Stroke-triggered BBB disruption was also reduced in mice when conivaptan treatments were initiated at 3 hours of reperfusion. However, 5 and 20-hour delays of conivaptan administration failed to reduce edema or protect BBB. Timing of conivaptan administration is important for successful reduction of brain edema and BBB disruption. Our experimental data open new possibilities to repurpose conivaptan, and make an important "bench-to-bedside translation" of the results into clinical practice.
doi_str_mv 10.1371/journal.pone.0183985
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Conivaptan, a V1a and V2 receptor antagonist, reduces brain edema and minimizes damage to the blood-brain barrier after stroke. Most stroke patients do not receive treatment immediately after the onset of brain ischemia. Delays in therapy initiation may worsen stroke outcomes. Therefore, we designed a translational study to explore the therapeutic time window for conivaptan administration. Mice were treated with conivaptan beginning 3, 5, or 20 hours after 60-minute focal middle cerebral artery occlusion. Treatments were administered by continuous IV infusion for a total of 48 hours. Brain edema and blood-brain barrier (BBB) disruption were evaluated at endpoint. Conivaptan therapy initiated at 3 hours following ischemia reduced edema in the ipsilateral hemisphere, which corresponded with improvements in neurological deficits. Stroke-triggered BBB disruption was also reduced in mice when conivaptan treatments were initiated at 3 hours of reperfusion. However, 5 and 20-hour delays of conivaptan administration failed to reduce edema or protect BBB. Timing of conivaptan administration is important for successful reduction of brain edema and BBB disruption. Our experimental data open new possibilities to repurpose conivaptan, and make an important "bench-to-bedside translation" of the results into clinical practice.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28854286</pmid><doi>10.1371/journal.pone.0183985</doi><tpages>e0183985</tpages><orcidid>https://orcid.org/0000-0002-1259-3136</orcidid><oa>free_for_read</oa></addata></record>
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1932-6203
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subjects Animals
Antidiuretic Hormone Receptor Antagonists - therapeutic use
Arginine
Argipressin
Argipressin receptors
Benzazepines - therapeutic use
Biology and Life Sciences
Blood-brain barrier
Blood-Brain Barrier - drug effects
Blood-Brain Barrier - pathology
Brain damage
Brain Edema - drug therapy
Brain Edema - etiology
Brain Edema - pathology
Brain injury
Brain research
Cerebral blood flow
Cerebral edema
Complications and side effects
Conivaptan hydrochloride
Critical care
Disruption
Dosage and administration
Drug dosages
Drug therapy
Edema
Experiments
Health aspects
Infarction, Middle Cerebral Artery - complications
Infarction, Middle Cerebral Artery - pathology
Ischemia
Laboratories
Male
Medical research
Medicine and Health Sciences
Metabolism
Mice
Mice, Inbred C57BL
Neurological diseases
Occlusion
Patient outcomes
Physiology
Reperfusion
Risk factors
Rodents
Stroke
Surgery
Therapy
Traumatic brain injury
Vasopressin
Veins & arteries
Windows (intervals)
title Therapeutic time window for conivaptan treatment against stroke-evoked brain edema and blood-brain barrier disruption in mice
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