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(Stroke. 2007;38:255.)
© 2007 American Heart Association, Inc.

Letters to the Editor

Molecular Mechanisms Underlying Neuroprotective Effects of Albumin After Ischemic Stroke

Jaakko Parkkinen, MD

Neuroscience Center, University of Helsinki, Helsinki, Finland

Pauli Ojala, Msci

Finnish Red Cross Blood Service, Helsinki, Finland

Jenni Niiranen, Msci Jukka Jolkkonen, PhD

Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland

To the Editor:

We read with great interest the recent articles by Dr Ginsberg et al¹ and Dr Palesch et al² reporting the results of a phase I clinical trial with human albumin infusion in stroke. It has been suggested that the beneficial effect observed by human albumin in the rodent stroke models is attributable to a contaminating plasma protein, ₁-acid glycoprotein (AGP).³ AGP mitigated brain edema in a rat model of global cerebral ischemia, in which AGP was given at a dose of 200 mg/kg 30 minutes after reperfusion. In their response, Ginsberg et al³ challenged this argument based on the limited amount of AGP potentially present in albumin preparations as compared with the doses found protective.

To further investigate the influence of AGP in transient focal ischemia, we have tested purified human plasma AGP in the same rat model of middle carotid artery occlusion (MCAo) as used in the studies which have demonstrated the efficacy of albumin. In our study, the right MCA was occluded for 2 hours. AGP was given intravenously at 2 doses, 50 and 200 mg/kg, 60 minutes after start of reperfusion. Functional outcome was assessed by the limb-placing test during the 3-day recovery period, and after that infarct volumes were measured from triphenyltetrazolium chloride (TTC)-stained sections. AGP doses that were tested did not affect functional or histological outcome in rats after MCAo. We conclude that AGP is not protective after transient focal cerebral ischemia at doses potentially present in pharmaceutical albumin products.

Considering the molecular mechanism underlying neuroprotective effects of albumin, we would like to pay attention to a lysolipid bound by albumin in circulation, lysophosphatidylcholine (lysoPC). Free lysoPC exerts potent proinflammatory actions including upregulation of leukocyte adhesion molecules and reduction of NO-dependent vasodilatation in vascular endothelium, induction of oxidative stress in smooth-muscle cells and chemotaxis and secretion of inflammatory mediators in monocytes and neutrophils.⁴ At higher concentrations it causes apoptotic cell death. LysoPC is generated through the action of phospholipase A₂ (PLA₂) on phosphatidylcholine in cell membranes and oxidized LDL (oxLDL).⁴ Of the several PLA₂ types occurring in tissues, the expression and activity of the cytosolic (cPLA₂) and secretory (sPLA₂) forms is increased in ischemic stroke, particularly in the penumbra region surrounding the ischemic core.⁵ Further, a causal contribution of cPLA₂ to ischemic brain injury has been demonstrated in gene knockout mice.⁵ A lipoprotein-associated PLA₂ (Lp-PLA₂) is transported in plasma predominantly in LDL. An increased plasma level of Lp-PLA₂ has been identified as an independent risk factor for stroke.⁴ Lp-PLA₂ acts on oxLDL, which is rich in lysoPC, and both oxLDL and lysoPC cause vasoconstriction in brain vasculature through the release of endothelin-1.⁶

Albumin has been shown to prevent lysoPC-induced permeability increase in endothelial cells in vitro, and albumin infusion into hypoalbuminemic rats prohibits lysoPC-mediated vasoconstriction. However, free fatty acids have a higher affinity to albumin than lysoPC, and fatty acids effectively displace lysoPC from albumin.⁷ Thus, in acute ischemic conditions, when the levels of both lysoPC and free fatty acids increase,⁸ the binding capacity of endogenous albumin for lysoPC may become saturated. Therefore, one of the protective mechanisms exerted by high-dose albumin infusion in ischemic stroke may be scavenging of the accumulating lysoPC and preventing its proinflammatory and proapoptotic effects.

Acknowledgments

Disclosures

None.

References

1. Ginsberg MD, Hill MD, Palesch YY, Ryckborst KJ, Tamariz D. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke-I: physiological responses and safety results. Stroke. 2006; 37: 2100–2106.[Abstract/Free Full Text]
2. Palesch YY, Hill MD, Ryckborst KJ, Tamariz D, Ginsberg MD. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke-II: neurologic outcome and efficacy analysis. Stroke. 2006; 37: 2107–2114.[Abstract/Free Full Text]
3. Muchitsch EM, Schwarz HP. Beneficial effect of albumin therapy attributable to 1-acid glycoprotein?; Ginsberg MD, Belayev L, Busto R. Response. Stroke. 2003; 34: 4–5.[Free Full Text]
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7. Ojala PJ, Hermansson M, Tolvanen M, Polvinen K, Hirvonen T, Impola U, Jauhiainen M, Somerharju P, Parkkinen J. Identification of alpha-1 acid glycoprotein as a lysophospholipid binding protein. Biochemistry. 2006; 45: 14021–14031.[CrossRef][Medline] [Order article via Infotrieve]
8. Kinouchi H, Imaizumi S, Yoshimoto T, Yamamoto H, Motomiya M. Changes of polyphosphoinositides, lysophospholipid, and free fatty acids in transient cerebral ischemia of rat brain. Mol Chem Neuropathol. 1990; 12: 215–228.[Medline] [Order article via Infotrieve]

This Article Full Text (PDF) All Versions of this Article: 38/2/255    most recent 01.STR.0000254506.06583.2dv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Parkkinen, J. Articles by Jolkkonen, J. Search for Related Content PubMed PubMed Citation Articles by Parkkinen, J. Articles by Jolkkonen, J. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Stroke