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

Abstract

J. Neurochem. (2012) 122, 321–332. 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.

Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke

“…We have recently shown that IVIg can be a potent neuroprotective therapy Widiapradja et al, 2012), so our next aim was to assess its effect on LRP1 in primary neurons. While it did not affect the expression levels of LRP1 under normal conditions and after 6 hours of OGD ( Fig.…”

“…The activation of NF-B, p38 MAPK and JNK pathways is key to ischemiainduced cellular stress responses and neuronal death Arumugam et al 2011;Widiapradja et al, 2012). Under this premise, we measured the levels and phosphorylation of NF-B-p65, p38 MAPK and JNK in RAP-treated primary neurons subjected to OGD with or without IVIg, to assess the interplay between LRP1 and IVIg pathways.…”

“…There are few treatment options available to minimize neuronal cell death following a stroke. We have recently identified intravenous immunoglobulin (IVIg) as a potent stroke therapy Widiapradja et al, 2012;Fann et al, 2013;Lok et al, 2015). IVIg preparations are fractionated from a plasma pool of healthy donors and contain both immune antibodies and physiologic autoantibodies.…”

“…Administration of IVIg to mice subjected to experimental ischemic stroke reduced mortality rates and infarct size Widiapradja et al, 2012). Moreover, IVIg can directly protect neurons against ischemic conditions by targeting inappropriately activated components of the innate immune system, such as the complement system and the toll like receptors (TLRs) Lok et al, 2015), and it can also protect brain endothelial cells from death (Widiapradja et al, 2014).…”

Acute Intravenous Infusion of Immunoglobulins Protects Against Myocardial Ischemia-Reperfusion Injury Through Inhibition of Caspase-3

“…IVIG were also found to be beneficial when used in a neuronal I/R model, inhibiting toll-like receptor-mediated responses and complement-mediated neuronal cell death [25, 26]. IVIG were also found to protect neurons against ischemic stroke via a pathway involving a reduction of caspase-3 cleavage and an elevation of the levels of the anti-apoptotic protein Bcl2 in cortical neurons [27]. …”