Published online before print December 12, 2002, doi: 10.1161/01.STR.0000046761.84916.64
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(Stroke. 2003;34:4.)
© 2003 American Heart Association, Inc.
Letters to the Editor |
Beneficial Effect of Albumin Therapy Attributable to 
1-Acid Glycoprotein?
Baxter BioScience, Vienna, Austria
To the Editor:
Belayev et al1 report that albumin therapy has the beneficial effect of reversing stagnation, thrombosis, and corpuscular adherence in the cortical venules of a rat model of middle cerebral artery occlusion. They cite further studies in which human serum albumin treatment conferred neurological and histological protection in rat stroke models of focal2–4 and global5 cerebral ischemia as well as traumatic brain injury.6
We have previously shown7 that human 
1-acid glycoprotein (orosomucoid), an acute phase protein, also has a beneficial effect in a rat model of global cerebral ischemia, even 30 minutes after reperfusion. In our study, human 1-acid glycoprotein was given IV in doses of 50, 200, and 600 mg/kg. Compared with control animals treated with placebo (albumin free of 1-acid glycoprotein), the doses of 200 and 600 mg/kg successfully mitigated brain edema.
The concentration of 1-acid glycoprotein in human plasma is about 0.2 to 1.4 mg/mL. One of its major physiological roles seems to be to maintain permeability of the capillary barrier,8 which is probably achieved by increasing the negative charge of the capillary endothelium9,10 and thus reducing the transvascular transport of polyanionic macromolecules. Increased vascular permeability is a common symptom in various kinds of shock, stroke, etc. A beneficial effect of 1-acid glycoprotein can therefore be anticipated under these pathophysiological conditions. Additionally, we have shown that resuscitation with human 1-acid glycoprotein effectively restores cardiac output and stroke volume in a rat model of hemorrhagic/hypovolemic shock11 by tightening the microvessel walls, thereby increasing the intravascular circulating volume.
During early postischemic reperfusion, there is a progressive accumulation of polymorphonuclear leukocytes in regions of low cerebral blood flow.12 It is known from in vitro studies with these leukocytes13,14 that 1-acid glycoprotein inhibits neutrophil aggregation and superoxide anion generation. Furthermore, 1-acid glycoprotein inhibits platelet aggregation15 and enables erythrocytes to pass through micropores,16 which probably improves altered rheologic conditions.
These studies in rat models of stroke point to the possibility that the beneficial effect of albumin treatment is attributable to the 1-acid glycoprotein content of albumin solution.
References
1. Belayev L, Pinard E, Nallet H, Seylaz J, Liu Y, Riyamongkol P, Zhao W, Busto R, Ginsberg MD. Albumin therapy of transient focal cerebral ischemia. Stroke. 2002; 33: 1077–1084.
2. Belayev L, Busto R, Zhao W, Clemens J, A, Ginsberg MD. Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats. J Neurosurg. 1997; 87: 595–601.[Medline] [Order article via Infotrieve]
3. Belayev L, Zhao W, Pattany PM, Weaver RG, Huh PW, Lin B, Busco R, Ginsberg MD. Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia. Stroke. 1998; 29: 2587–2599.
4. Belayev L, Liu Y, Zhao W, Busco R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with broad therapeutic window. Stroke. 2001; 32: 553–560.
5. Belayev L, Saul I, Huh PW, Finolti N, Zhao W, Busco R, Ginsberg MD. Neuroprotective effect of high-dose albumin therapy against global ischemic brain injury in rats. Brain Res. 1999; 845: 107–111.[CrossRef][Medline] [Order article via Infotrieve]
6. Belayev L, Alonso OF, Huh PW, Zhao W, Busco R, Ginsberg MD. Posttreatment with high-dose albumines reduces histopathological damage and improves neurological deficit following fluid percussion brain injury in rats. J Neurotrauma. 1999; 16: 445–453.[Medline] [Order article via Infotrieve]
7. Pichler L, Muchitsch EM, Schwarz HP. Präklinische Untersuchung von 1-saurem Glykoprotein (Orosomucoid). Wien Klin Wochenschr. 1999; 111/5: 192–198.
8. Haraldsson B, Rippe B. Orosomucoid as one of the serum components contributing to normal capillary permselectivity in rat skeletal muscle. Acta Physiol Scand. 1987; 129: 127–135.[Medline] [Order article via Infotrieve]
9. Curry FE, Rutledge JC, Lenz JF. Modulation of microvessel wall charge by plasma glycoprotein orosomucoid. Am J Physiol. 1989; 257: H1354–H1359.[Medline] [Order article via Infotrieve]
10. Schnitzer JE, Pinney E. Quantitation of specific binding of orosomucoid to cultured microvascular endothelium: Role in capillary permeability. Am J Physiol. 1992; 263: H48–H55.[Medline] [Order article via Infotrieve]
11. Muchitsch EM, Auer W, Pichler L. Effects of 1-acid glycoprotein in different models of shock. Fundam Clin Pharmacol. 1998; 12: 173–181.[Medline]
[Order article via Infotrieve]
12. Hallenbeck JM, Dutka AJ, Tanishima T, Kochanek PM, Kumaroo KK, Thompson CB, Obrenovich TP, Contreras TJ. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke. 1986; 17: 246–253.
13. Costello MJ, Gewurz H, Siegel JN. Inhibition of neutrophil activation by 1-acid glycoprotein. Clin Exp Immunol. 1984; 55: 465–472.[Medline]
[Order article via Infotrieve]
14. Vasson MP, Roch-Arveiller M, Couderc R, Baguet JC, Raichvarg D. Effect of 1-acid glycoprotein on human polymorphonuclear neutrophils: influence of glycan microheterogeneity. Clinica Chimica Acta. 1994; 224: 65–71.[CrossRef][Medline]
[Order article via Infotrieve]
15. Costello M, Fiedel BA, Gewurz H. Inhibition of platelet aggregation by native and desialized 1-acid glycoprotein. Nature. 1979; 281: 677–678.[CrossRef][Medline]
[Order article via Infotrieve]
16. Maeda H, Morinaga T, Mori I, Nishi K. Further characterization of the effects of alpha 1-acid glycoprotein on the passage of human erythrocytes through micropores. Cell Struct Funct. 1984; 9: 279–290.[Medline] [Order article via Infotrieve]
Department of Neurology, University of Miami School of Medicine, Miami, Fla
Response
We appreciate the interesting response of Drs Muchitsch and Schwarz, describing the salutary properties of 1-acid glycoprotein in mitigating cerebral edema, combating abnormal increases in microvascular permeability, and inhibiting neutrophil aggregation. These investigators raise the intriguing speculation that the beneficial effect of albumin solution might be attributable to its 1-acid glycoprotein content. However, their own data would suggest that this is probably not the case: using the authors’ mean value of 
0.8 mg/mL for the concentration of 1-acid glycoprotein in human plasma (a value consistent with the published literature4) and a normal value for albumin in human plasma of 4.4 g/dL, it follows that human plasma would be predicted to contain 0.02 mg of 1-acid glycoprotein per mg of albumin. Our own previous studies1 show that human albumin is highly neuroprotective in focal ischemia even at 1.25 g/kg, ie, one-half the concentration of 2.5 g/kg used in the present study.2 According to the above computations, 1.25 to 2.5 g/kg of albumin would contain only 25 to 50 mg/kg of 1-acid glycoprotein—a level far below the 200 to 600 mg/kg dose reported by these authors as required to reduce brain edema.3 The direct test of their hypothesis, however, would be the use of an albumin preparation free of 1-acid glycoprotein.
References
1. Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke. 2001; 32: 553–560.
2. Belayev L, Pinard E, Nallet H, Seylaz J, Liu Y, Riyamongkol P, Zhao W, Busto R, Ginsberg MD. Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke. 2002; 33: 1077–1084.
3. Pichler L, Muchitsch EM, Schwarz HP. Praeklinische untersuchung von 1-saurem glykoprotein (Orosomucoid). Wien Klin Wochenschr. 1999; 111: 192–198.[Medline]
[Order article via Infotrieve]
4. Young RC, Patel A, Meyers BS, Kakuma T, Alexopoulos GS. 1-acid glycoprotein, age, and sex in mood disorders. Am J Geriatr Psychiatry. 1999; 7: 331–334.[Medline]
[Order article via Infotrieve]
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