La infusión intravenosa continua es la Ruta Opción de tratamiento para la arginina vasopresina-bloqueante del receptor Conivaptan en ratones para Stroke Study-evocó edema cerebral
Summary
Our studies have revealed that the beneficial effects of conivaptan are dependent on the method of delivery after experimental stroke in mice. We have developed a research protocol for delivery of the receptor blocker via IV catheter on stroke-evoked brain edema formation in mice.
Abstract
El accidente cerebrovascular es una de las principales causas de morbilidad y mortalidad en el mundo. El accidente cerebrovascular es complicada por el edema cerebral y otros eventos fisiopatológicos. Entre los jugadores más importantes en el desarrollo y evolución del edema cerebral derrame cerebral evocada es la hormona arginina-vasopresina y sus receptores V1a, y V2. Recientemente, el antagonista de los receptores V1a conivaptán y V2 ha estado atrayendo la atención como un posible fármaco para reducir el edema cerebral tras un accidente cerebrovascular. Sin embargo, los modelos animales que impliquen aplicaciones conivaptán en investigación del accidente cerebrovascular deben ser modificados con base en las rutas posibles de administración. Aquí los resultados de 48 hr intravenosa continua (IV) se comparan con los tratamientos intraperitoneal (IP) conivaptán después del accidente cerebrovascular experimental en ratones. Hemos desarrollado un protocolo en el que la oclusión de la arteria cerebral media se combinó con la instalación del catéter en la vena yugular para el tratamiento IV de conivaptán (0,2 mg) o vehículo. Diferentes cohortes de animales se trataron con 0,2mg bolo de conivaptán o vehículo IP diaria. Experimental edema cerebral derrame cerebral evocada se evaluó en ratones después de IV continua y tratamientos IP. Comparación de los resultados reveló que la administración IV continua de conivaptán alivia edema cerebral post-isquémico en ratones, a diferencia de la administración IP de conivaptán. Llegamos a la conclusión de que nuestro modelo puede ser utilizado para futuros estudios de aplicaciones conivaptán en el contexto de accidente cerebrovascular y edema cerebral.
Introduction
Stroke continues to be an enormous burden for patients and clinicians. Animal stroke models have been used in the laboratory setting for nearly two decades.1 Nevertheless, experimental treatments that work in animals often fail in humans.2 This discrepancy in treatment outcomes may be due to various factors, such as administration routes for drugs used in animal research, drug metabolism and elimination rate, and many other aspects. One of the major complications of stroke, brain edema, is a focus of current research in neuroscience. Mechanisms of brain edema formation involve disturbances in water and electrolyte balance triggered by the arginine-vasopressin (AVP) response to ischemic brain injury.3 Therefore, AVP and its receptors (V1a and V2) are a major focus of research studies of post-ischemic brain edema formation.3
We have developed a methodology to study the effects of mixed arginine-vasopressin (V1a and V2) receptor blocker conivaptan on post-ischemic brain edema in mice.4 Molecular targets of conivaptan5 make the drug a suitable candidate for exploration of its properties in alleviation of brain edema. Furthermore, conivaptan needs to be studied in the context of pathophysiological events of stroke.6 In designing this study, we considered comparing treatment outcomes using two different routes of administration for conivaptan: intravenous (IV)4 and intraperitoneal (IP).7 Effects of the treatments on stroke-induced brain edema were evaluated. Here detailed protocols are described for surgical induction of experimental stroke by middle cerebral artery occlusion (MCAO), and followed by continuous conivaptan treatment using the installation of a jugular IV catheter. After induction of stroke, animals were randomly allocated into the following groups: vehicle or conivaptan (0.2 mg/day) treated IV or IP.
Protocol
Representative Results
Discussion
Este estudio tiene un valor importante para la investigación preclínica accidente cerebrovascular. Este estudio revela que la infusión IV continua de conivaptán (0,2 mg / día) después del accidente cerebrovascular experimental en ratones reduce eficazmente el edema cerebral después de 48 h de tratamiento. También se investigó el efecto de la inyección IP de la misma dosis de conivaptán en edema cerebral. tratamiento Conivaptan por ambas IV e IP rutas produce acuaresis en ratones, como se indica por: 1) aument…
Disclosures
The authors have nothing to disclose.
Acknowledgements
Agradecemos a Swedish Medical Center para proporcionar los fondos e instalaciones. También agradecemos a Craig Hospital para el uso generoso de espacio de laboratorio.
Materials
| Heated Pad | K&H Manufacturing Inc | 1060 | |
| Temperature Monitor with Rectal Probe | Physitemp | 7029 | |
| Silk Suture Spool, 6-0 | Surgical Specialties Corporation | SP114 | |
| Silk Suture on a Needle, 3-0 | Ethicon | 1684G | |
| Nylon Suture, 7-0 | Ethicon | 1696G | |
| Dental Resin Polysiloxane with Hardener | Heraeus Kulzer | 65817930 | |
| Microinfusion IV Pump | Kent Scietific | GT0897 | |
| Swivel 22GA | Instech | 375/22PS | |
| Laboratory Tubing, 0.94 x 0.51 mm | Dow Corning | 508-002 | |
| Laboratory Tubing, 3.18 x 1.98 mm | Dow Corning | 508-009 |
References
- Gueniau, C., Oberlander, C. The kappa opioid agonist niravoline decreases brain edema in the mouse middle cerebral artery occlusion model of stroke. J Pharmacol Exp Ther. 282, 1-6 (1997).
- Krafft, P. R., et al. Etiology of stroke and choice of models. Int J Stroke. 7, 398-406 (2012).
- Vakili, A., Kataoka, H., Plesnila, N. Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 25, 1012-1019 (2005).
- Zeynalov, E., Jones, S. M., Seo, J. W., Snell, L. D., Elliott, J. P. Arginine-Vasopressin Receptor Blocker Conivaptan Reduces Brain Edema and Blood-Brain Barrier Disruption after Experimental Stroke in Mice. PloS one. 10, e0136121 (2015).
- Med Lett Drugs Ther.. Conivaptan (Vaprisol) for hyponatremia. The Medical letter on drugs and therapeutics. 48, 51-52 (2006).
- Zhao, X. Y., et al. Effect of arginine vasopressin on the cortex edema in the ischemic stroke of Mongolian gerbils. Neuropeptides. 51, 55-62 (2015).
- Manaenko, A., Chen, H., Kammer, J., Zhang, J. H., Tang, J. Comparison Evans Blue injection routes: Intravenous versus intraperitoneal, for measurement of blood-brain barrier in a mice hemorrhage model. J Neurosci Methods. 195, 206-210 (2011).
- Adams, S., Pacharinsak, C. Mouse anesthesia and analgesia. Curr Protoc Mouse Biol. 5, 51-63 (2015).
- Zeynalov, E., et al. The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema. Crit Care Med. 36, 2634-2640 (2008).
- Zeynalov, E., Dore, S. Low doses of carbon monoxide protect against experimental focal brain ischemia. Neurotox Res. 15, 133-137 (2009).
- Zeynalov, E., Nemoto, M., Hurn, P. D., Koehler, R. C., Bhardwaj, A. Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide. J Cereb Blood Flow Metab. 26, 414-420 (2006).
- Ma, M. C., Qian, H., Ghassemi, F., Zhao, P., Xia, Y. Oxygen-sensitive {delta}-opioid receptor-regulated survival and death signals: novel insights into neuronal preconditioning and protection. J Biol Chem. 280, 16208-16218 (2005).
- Ahmad, M., Zhang, Y., Liu, H., Rose, M. E., Graham, S. H. Prolonged opportunity for neuroprotection in experimental stroke with selective blockade of cyclooxygenase-2 activity. Brain Res. 1279, 168-173 (2009).
- Meisel, C., et al. Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke. Stroke. 35, 2-6 (2004).
- Miner, N. A., Koehler, J., Greenaway, L. Intraperitoneal injection of mice. Appl Microbiol. 17, 250-251 (1969).
- Adis International Limited. Conivaptan: YM 087. Drugs in R&D. 5, 94-97 (2004).
- Murphy, T., Dhar, R., Diringer, M. Conivaptan bolus dosing for the correction of hyponatremia in the neurointensive care unit. Neurocrit Care. 11, 14-19 (2009).
- Liu, X., Nakayama, S., Amiry-Moghaddam, M., Ottersen, O. P., Bhardwaj, A. Arginine-vasopressin V1 but not V2 receptor antagonism modulates infarct volume, brain water content, and aquaporin-4 expression following experimental stroke. Neurocrit Care. 12, 124-131 (2010).
- Wallace, B. K., Jelks, K. A., O’Donnell, M. E. Ischemia-induced stimulation of cerebral microvascular endothelial cell Na-K-Cl cotransport involves p38 and JNK MAP kinases. Am J Physiol Cell Physiol. 302, C505-C517 (2012).
- O’Donnell, M. E., et al. Intravenous HOE-642 reduces brain edema and Na uptake in the rat permanent middle cerebral artery occlusion model of stroke: evidence for participation of the blood-brain barrier Na/H exchanger. J Cereb Blood Flow Metab. 33, 225-234 (2013).
- Walcott, B. P., Kahle, K. T., Simard, J. M. Novel treatment targets for cerebral edema. Neurotherapeutics. 9, 65-72 (2012).
- Shen, Z., et al. Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury. CNS Neurosci Ther. 21, 271-279 (2015).
