The goal of this project is increase tissue rescue from stroke by improving O2 delivery with the use of cell- free hemoglobin (Hb) O2 carriers (HBOC) and agents that simultaneously improve collateral blood flow. An early clinical attempt to use the first generation of crosslinked tetrameric Hb was not successful partially because of unwanted side effects related to scavenging of the vasodilator, nitric oxide (NO), and production of the vasoconstrictor, endothelin. Our previous work demonstrated that polymerization of Hb avoided some of these side effects and rescued tissue from stroke in animals. However, dilation of pial arteries in the distal ischemic territory adjacent to anastomotic vessels was not sustained, perfusion was not improved, and tissue rescue was likely submaximal. Preliminary data indicated that dilation of these arteries could be better sustained during prolonged ischemia by co-administration of an inhibitor of arginase, an enzyme that can constrain endothelial NO production and promote superoxide generation by uncoupled NO synthase, or by co-administration of nitrite, which enables the NO scavenged by Hb to be recycled by virtue of the nitrite reductase activity of Hb. Moreover, Hb decorated with polyethylene glycol (PEG-Hb) may be superior to previously tested polymerized Hb because of its higher oncotic pressure and viscosity, which promotes endothelial shear stress-induced NO production. Indeed, transfusion of PEG-Hb during early transient focal ischemia was found to markedly reduce cortical infarct volume by 83%. Moreover, polynitroxylation of PEG- Hb, which confers antioxidant properties and limits formation of highly reactive ferryl Hb, was found to improve intraischemic dilation of pial arteries and to rescue cortex by 89%.
Aim 1 of this proposal is to optimize the transfusion protocol and dose of PEG-Hb and polynitroxylated PEG-Hb and determine if polynitroxylation provides added benefit in a more severe model of transient ischemia and in an embolic clot model.
Aim 2 is to better understand the role of arginase activity in the progressive loss of vasodilation in the ischemic border region.
This aim will reveal if an arginase inhibitor reduces endothelial oxidative stress and if co-administration with the HBOC that was optimal in Aim 1 provides additional vasodilation, improved blood flow, and tissue rescue.
Aim 3 is to determine if co-administration of nitrite with an HBOC also provides additional vasodilation and tissue rescue. Using the most efficacious vasodilating agents, HBOC product, and transfusion protocol seen in Aims 1-3, the therapeutic window of opportunity, long-term outcome and gender effects will be investigated in an embolic clot model of stroke in Aim 4. Therefore, this proposal will capitalize on more recent advances in our knowledge of the properties of HBOC and vascular control mechanisms to optimize O2 delivery and maximize tissue rescue from ischemic stroke. Results from these studies have the potential to be translated into clinical therapy for the acute treatment of stroke, a disease with high mortality and devastating disabilities that represent a large burden on society.
Stroke is the third leading cause of death, and the disabilities that remain in survivors place a major burden on society. In experimental models of stroke, we will investigate the use of chemically modified hemoglobin molecules, which are endowed with unique physical and antioxidant properties, as transfusion fluids that enable more oxygen to be delivered to the injured brain without adding to the oxidant stress of the stroke. We will also investigate drugs that can dilate arteries and permit more blood flow and oxygen to be delivered selectively to the injured brain when administered together with the hemoglobin solution and thereby enhance rescue of tissue from ischemic stroke.
|Papangelou, Alexander; Toung, Thomas J K; Gottschalk, Allan et al. (2013) Infarct volume after hyperacute infusion of hypertonic saline in a rat model of acute embolic stroke. Neurocrit Care 18:106-14|
|Li, Mingchang; Zhang, Zhan; Sun, Weiyun et al. (2011) 17ýý-estradiol attenuates breakdown of blood-brain barrier and hemorrhagic transformation induced by tissue plasminogen activator in cerebral ischemia. Neurobiol Dis 44:277-83|
|Texel, Sarah J; Zhang, Jian; Camandola, Simonetta et al. (2011) Ceruloplasmin deficiency reduces levels of iron and BDNF in the cortex and striatum of young mice and increases their vulnerability to stroke. PLoS One 6:e25077|
|Sakata, Yoshihito; Zhuang, Hean; Kwansa, Herman et al. (2010) Resveratrol protects against experimental stroke: putative neuroprotective role of heme oxygenase 1. Exp Neurol 224:325-9|
|Klaus, Judith A; Kibler, Kathleen K; Abuchowski, Abraham et al. (2010) Early treatment of transient focal cerebral ischemia with bovine PEGylated carboxy hemoglobin transfusion. Artif Cells Blood Substit Immobil Biotechnol 38:223-9|
|Renic, Marija; Klaus, Judith A; Omura, Tomohiro et al. (2009) Effect of 20-HETE inhibition on infarct volume and cerebral blood flow after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 29:629-39|
|Fronticelli, Clara; Koehler, Raymond C (2009) Design of recombinant hemoglobins for use in transfusion fluids. Crit Care Clin 25:357-71, Table of Contents|
|Mito, Toshiaki; Nemoto, Masaaki; Kwansa, Herman et al. (2009) Decreased damage from transient focal cerebral ischemia by transfusion of zero-link hemoglobin polymers in mouse. Stroke 40:278-84|
|Cao, Suyi; Wang, Liang-Chao; Kwansa, Herman et al. (2009) Endothelin rather than 20-HETE contributes to loss of pial arteriolar dilation during focal cerebral ischemia with and without polymeric hemoglobin transfusion. Am J Physiol Regul Integr Comp Physiol 296:R1412-8|
|Koehler, Raymond C; Fronticelli, Clara; Bucci, Enrico (2008) Insensitivity of cerebral oxygen transport to oxygen affinity of hemoglobin-based oxygen carriers. Biochim Biophys Acta 1784:1387-94|
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