Hemoglobin-Induced Oxidative Stress Contributes to Matrix Metalloproteinase Activation and Blood–Brain Barrier Dysfunction in vivo

Abstract

Hemoglobin (Hb) released from extravasated erythrocytes is implicated in brain edema after intracerebral hemorrhage (ICH). Hb is a major component of blood and a potent mediator of oxidative stress after ICH. Oxidative stress and matrix metalloproteinases (MMPs) are associated with blood-brain barrier (BBB) dysfunction. This study was designed to elucidate whether Hb-induced oxidative stress contributes to MMP-9 activation and BBB dysfunction in vivo. An intracerebral injection of Hb into rat striata induced increased hydroethidine (HEt) signals in parallel with MMP-9 levels. In situ gelatinolytic activity colocalized with oxidized HEt signals in vessel walls, accompanied by immunoglobulin G leakage and a decrease in immunoactivity of endothelial barrier antigen, a marker of endothelial integrity. Administration of a non-selective MMP inhibitor prevented MMP-9 levels and albumin leakage in injured striata. Moreover, reduction in oxidative stress by copper/zinc-superoxide dismutase (SOD1) overexpression reduced oxidative stress, MMP-9 levels, albumin leakage, and subsequent apoptosis compared with wild-type littermates. We speculate that Hb-induced oxidative stress may contribute to early BBB dysfunction and subsequent apoptosis, partly through MMP activation, and that SOD1 overexpression may reduce Hb-induced oxidative stress, BBB dysfunction, and apoptotic cell death.

Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice

“…In particular, Hb causes secondary damage via oxidative stress and has been implicated in further perpetuating cell death. 4 Recently, stem cell transplants have emerged as an exciting avenue for further research with potential clinical applications. Studies have shown the neuroprotection of intraparenchymal cell transplants that can ameliorate primary and secondary injury in animals with ICH, as well as enhance functional recovery.…”

Transplantation of Neural Stem Cells That Overexpress Sod1 Enhances Amelioration of Intracerebral Hemorrhage in Mice

“…26,27 Injection of autologous lysed erythrocytes, Hb, and iron into the brain produces ROS, causing brain damage in animal models. 14,28,29 In this study, we demonstrated that (i) Hb led to NSC death via ROS production, which may also mediate grafted cell death in ICH; (ii) overexpression of SOD1 in NSCs reduced ROS and increased survival of these cells after exposure to Hb and after transplantation in the ICH brain; and (iii) transplantation of SOD1 Tg NSCs enhanced neuroprotection and facilitated behavioral recovery in mice with ICH. Although the vulnerability and response of NSCs to Hb cytotoxicity have not yet been examined, several studies have shown a rapid and massive loss of NSCs under oxidative stress.…”

“…We have shown that SOD1 overexpression reduces oxidative stress induced by Hb, resulting in the reduction of blood-brain barrier disruption and the decrease in apoptotic cell death in the rat brain. 14 We have also reported that transplantation of neural stem cells (NSCs) that overexpress SOD1 provides extended survival of these grafted cells and facilitates functional recovery in ischemic stroke animals. 15 The purpose of this study was to determine whether ROS cause grafted cell death and whether SOD1 overexpression in NSCs can increase their survival after early transplantation in mice with ICH and can enhance functional recovery.…”

Structure and immune expression analysis of hemoglobin genes from the blood clam Tegillarca granosa

“…Hemoglobin (Hb) is also a source of antibacterial peptides in many animals; intact hemoglobin and its fractions exhibit antimicrobial activity against Gram-positive and -negative bacteria (Parish et al, 2001;Nedjar-Arroume et al, 2008). Human Hb can induce oxidative stress that may contribute to MMP-9 activation and BBB dysfunction, leading to apoptosis in vivo (Katsu et al, 2010).…”