持续静脉注射是精氨酸加压素受体拮抗剂考尼伐坦的选择治疗途径小鼠来研究中风诱发脑水肿
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
中风是在世界发病和死亡的主要原因之一。中风是脑水肿等病理生理事件复杂化。间在中风诱发的脑水肿的发展和演变的最重要的球员是激素精氨酸加压素及其受体，V1a和V2。最近，V1a和V2受体阻滞剂考尼伐坦受到关注作为潜在的药物，以减少中风后的脑水肿。然而，这在中风研究涉及考尼伐坦应用动物模型需要根据给药可行途径进行修改。在这里，48小时连续静脉注射（IV）的结果与小鼠实验中风后腹腔内（IP）考尼伐坦治疗相比。我们开发了在大脑中动脉闭塞与导管安装组合为IV治疗考尼伐坦（0.2毫克）或车辆的颈静脉的协议。动物的不同队列，用0.2治疗考尼伐坦或车辆的IP毫克，每天丸。实验中风诱发脑水肿连续IV和IP处理后的小鼠进行了评估。的结果比较，可知考尼伐坦的连续IV施用减轻小鼠局部缺血后的脑水肿，与考尼伐坦的IP施用。我们得出结论，我们的模型，可用于在中风和脑水肿的上下文考尼伐坦应用今后的研究。
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
这项研究有临床前研究中风重要的价值。这项研究表明，小鼠实验中风后考尼伐坦（0.2毫克/天）的持续静脉注射，有效降低治疗后的48小时脑水肿。 IP注射相同剂量对脑水肿考尼伐坦的效果也进行了研究。考尼伐坦治疗由双方IV和IP路由产生aquaresis由所示小鼠：1）血浆渗透压略高于生理水平的提高;和2）在尿渗透压降低由于在肾水再吸收的堵塞。因此，基于对治疗结果，我们报告中指出，四交付方…
Disclosures
The authors have nothing to disclose.
Acknowledgements
我们感谢瑞典医疗中心提供资金和设施。我们也感谢克雷格医院的大量使用的实验室空间。
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).
