Albumin Therapy of Transient Focal Cerebral Ischemia

Abstract

Background and Purpose-To study whether intravascular or hemodynamic factors contribute to the marked neuroprotective effect of albumin therapy in focal cerebral ischemia, 2 complementary methods were applied: laser-scanning confocal microscopy (LSCM) and laser-Doppler perfusion imaging (LDPI). Methods-In the LSCM study, Sprague-Dawley rats were anesthetized with halothane/nitrous oxide, and a cranial window was placed over the dorsolateral frontoparietal cortex. Rats received 2-hour middle cerebral artery occlusion (MCAO) by an intraluminal suture and were treated with human albumin (1.25 g/kg; nϭ4) or saline (nϭ3) after 30 minutes of recirculation. Video images of cortical vessels were continually acquired and were digitized offline to measure diameters and fluorescent erythrocyte velocities. In the LDPI study, cortical perfusion was measured in anesthetized SpragueDawley rats that received 2-hour MCAO and were treated with albumin (2.5 g/kg; nϭ6) or saline (nϭ5) at 30 minutes after recirculation. Results-In the LSCM study, MCAO was associated with arteriolar dilation and slowing of capillary and venular erythrocyte perfusion. During the first 15 to 30 minutes of postischemic recirculation, prominent foci of vascular stagnation developed within cortical venules, associated with thrombuslike foci and adherent corpuscular structures consistent in size with neutrophils. Saline administration failed to affect these phenomena, while albumin therapy was followed by significant increases in arteriolar diameter (Ϸ12%; Pϭ0.007) and by a prompt improvement of venular and capillary erythrocyte perfusion and a partial disappearance of adherent thrombotic material. Albumin therapy increased erythrocyte flow velocity in both capillaries (288Ϯ73% versus 76Ϯ18% in the saline group; Pϭ0.023) and venules (2.7-fold [Pϭ0.001] versus 1.0-fold in the saline group [PϭNS]). In the LDPI study, cortical perfusion declined during MCAO and rose initially with recirculation (to Ϸ135% of baseline) in both groups. Mean cortical perfusion improved slightly (Ϸ14%; PϭNS) in albumin-treated animals. Conclusions-These results reveal a beneficial effect of albumin therapy in reversing stagnation, thrombosis, and corpuscular adherence within cortical venules in the reperfusion phase after focal ischemia and support its utility in the treatment of acute ischemic stroke.

Polynitroxyl Albumin and Albumin Therapy after Pediatric Asphyxial Cardiac Arrest: Effects on Cerebral Blood Flow and Neurologic Outcome

“…Similar to our findings with PNA, SOD administration reduced early postresuscitation hyperemia in an asphyxial CA model in dogs (Cerchiari et al, 1987), and administration of SOD-albumin complex improved blood flow and neurologic outcome in a global ischemia-reperfusion model (Takeda et al, 1993). Similar to our study, albumin was shown to improve cortical perfusion after permanent focal cerebral ischemia (Liu et al, 2001) and improved perfusion in the microcirculation during the postischemic reperfusion period (Belayev et al, 2002). One possible explanation for our findings is mitigation of superoxide-induced vascular dysfunction by PNA versus albumin.…”

“…A beneficial effect of albumin in neurologic pathologies is suggested by studies in stroke and traumatic brain injury in which lower serum albumin levels are associated with poor outcome (Bernard et al, 2008;Idicula et al, 2009). Albumin has beneficial effects in animal models of focal ischemia (Belayev et al, 1997(Belayev et al, , 2002Liu et al, 2001); however, it was not found to be neuroprotec- tive either in a neonatal model of stroke or after clinical traumatic brain injury in adults (Myburgh et al, 2007;Wang et al, 2007). Albumin's beneficial effects for focal ischemia-reperfusion are attributed to antioxidant properties, inhibition of copper-induced peroxidation, fatty acid oxidation Rowley et al, 1984;Yao et al, 2010), binding of fatty acids and heme, and early upregulation of vascular endothelial growth factor (Yao et al, 2010).…”

“…In our pediatric asphyxial CA model, PNA decreased oxidative and nitrative stress induced by resuscitation with 100% oxygen (Walson et al, 2011). Albumin, the parent compound of PNA, has also been shown to improve perfusion and functional outcome in models of focal cerebral ischemia (Belayev et al, 1997(Belayev et al, , 1998(Belayev et al, , 2002Liu et al, 2001). Besides colloidal properties, albumin binds redoxactive transition metals, fatty acids, and heme and has some antioxidant properties due to a free cysteine residue Rowley et al, 1984).…”

fMRI of Delayed Albumin Treatment during Stroke Recovery in Rats: Implication for Fast Neuronal Habituation in Recovering Brains

“…Similar to other agents such as basic fibroblast growth factor (bFGF) (Kawamata et al, 1997), albumin treatment has been proposed to preserve the blood-brain barrier and contribute to stroke recovery via neuroprotective properties. In particular, albumin has been clearly shown to improve microvascular hemodynamics and to exert proendothelial effects (Belayev et al, 2002). In this study, we test whether delayedalbumin treatment improves the overall outcome of recovering ischemic brains using functional magnetic resonance imaging (fMRI) to characterize the treatment efficacy.…”

Estrogen Restores Postischemic Sensitivity to the Thromboxane Mimetic U46619 in Rat Pial Artery

“…Cerebral ischemia results in vascular abnormalities, such as hyperemia, residual hypoperfusion (Uhl et al, 2000;Belayev et al, 2002;Pulsinelli et al, 1983), and microcirculatory dysfunction (Clavier et al, 1994;Cipolla et al, 1997;Pulsinelli et al, 1982). Striking endothelial defects in vasodilation and constriction have been described (Rosenblum, 1988;Dietrich, 1994;Rosenblum and Wormley, 1995;Cipolla et al, 1997;Watanabe et al, 2001).…”