Intravenous immunoglobulin protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways

• Published in: Journal of neurochemistry 2012-07, Vol.122 (2), p.321-332
• Main Authors: Widiapradja, Alexander, Vegh, Viktor, Lok, Ker Zhing, Manzanero, Silvia, Thundyil, John, Gelderblom, Mathias, Cheng, Yi-Lin, Pavlovski, Dale, Tang, Sung-Chun, Jo, Dong-Gyu, Magnus, Tim, Chan, Sic L., Sobey, Christopher G., Reutens, David, Basta, Milan, Mattson, Mark P., Arumugam, Thiruma V.
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - pharmacology; Amyloid beta-Peptides - toxicity; Animals; apoptosis; Biological and medical sciences; Blotting, Western; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Brain Mapping; Cell Death - drug effects; Cell Hypoxia - drug effects; Cell Survival - drug effects; Cells; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Glucose - deficiency; Immunoglobulins; Immunoglobulins, Intravenous - pharmacology; Immunohistochemistry; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery - pathology; IVIg; Magnetic Resonance Imaging; Male; Medical sciences; Mice; Mice, Inbred C57BL; Neurology; Neurons; Neurons - drug effects; Neuroprotective Agents; Peptide Fragments - pharmacology; Peptides; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Signal Transduction - drug effects; Stroke; Stroke - pathology; Stroke - prevention & control; Toxicity; Treatment Outcome; Up-Regulation; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2012.07754.x

J. Neurochem. (2012) 122, 321–332. 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. Intravenous immunoglobulin for Stroke Intravenous immunoglobulin(IVIg) is a therapeutic modality approved for the treatment of various condition. This study was performed in order to understand the mechanism ofhow IVIg elicits its neuroprotective effect in stroke and amyloid beta induced neuronal apoptosis. The findings from this study showed that IVIg elicits its neuroprotective effects by not only inhibiting the cell death pathways but also elevating the anti‐apoptotic protein Bcl2. This study provides a better understanding of how IVIg plays a role in neuroprotection and therefore provides more evidence to encourage the use of IVIg as therapeutic modality in stroke and Alzheimer’s disease.