title: Intravenous immunoglobulin protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways.
abstract: Intravenous immunoglobulin (IVIg) preparations obtained by fractionating blood plasma, are increasingly being used increasingly as an effective therapeutic agent in treatment of several inflammatory diseases. Its use as a potential therapeutic agent for treatment of stroke and Alzheimer's disease has been proposed, but little is known about the neuroprotective mechanisms of IVIg. In this study, we investigated the effect of IVIg on downstream signaling pathways that are involved in neuronal cell death in experimental models of stroke and Alzheimer's disease. Treatment of cultured neurons with IVIg reduced simulated ischemia- and amyloid βpeptide (Aβ)-induced caspase 3 cleavage, and phosphorylation of the cell death-associated kinases p38MAPK, c-Jun NH2 -terminal kinase and p65, in vitro. Additionally, Aβ-induced accumulation of the lipid peroxidation product 4-hydroxynonenal was attenuated in neurons treated with IVIg. IVIg treatment also up-regulated the anti-apoptotic protein, Bcl2 in cortical neurons under ischemia-like conditions and exposure to Aβ. Treatment of mice with IVIg reduced neuronal cell loss, apoptosis and infarct size, and improved functional outcome in a model of focal ischemic stroke. Together, these results indicate that IVIg acts directly on neurons to protect them against ischemic stroke and Aβ-induced neuronal apoptosis by inhibiting cell death pathways and by elevating levels of the anti-apoptotic protein Bcl2.
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Widiapradja
authors.forename: Viktor
authors.initials: V
authors.lastname: Vegh
authors.forename: Ker Zhing
authors.initials: KZ
authors.lastname: Lok
authors.forename: Silvia
authors.initials: S
authors.lastname: Manzanero
authors.forename: John
authors.initials: J
authors.lastname: Thundyil
authors.forename: Mathias
authors.initials: M
authors.lastname: Gelderblom
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Cheng
authors.forename: Dale
authors.initials: D
authors.lastname: Pavlovski
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Sic L
authors.initials: SL
authors.lastname: Chan
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.forename: David
authors.initials: D
authors.lastname: Reutens
authors.forename: Milan
authors.initials: M
authors.lastname: Basta
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D001931:Brain Mapping; D016923:Cell Death / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D010446:Peptide Fragments / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D016756:Immunoglobulins, Intravenous; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C075222:amyloid beta-protein (1-42); D005947:Glucose