Anti-Porin Antibodies Prevent Excitotoxic and Ischemic Damage to Brain Tissue

Velázquez, José Luis Pérez; Kokarovtseva, Larisa; Weisspapir, Michael; Frantseva, Marina

doi:10.1089/089771503322144554

Cited by 9 publications

(7 citation statements)

References 75 publications

(86 reference statements)

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“…This is in contrast to previous studies reporting that down-regulating PHB exacerbated neuronal cell death following oxidative stress and L-glutamic acid exposure [12]. In addition, treat ment of rat brain slices with an anti-VDAC1 antibody reduces neuronal death following in vitro ischemia and L-glutamic acid excitotoxicity [13]. These discrepancies could be related to differences in the cell cultures and injury models used, and the degree of protein down-regulation.…”

Section: Discussioncontrasting

confidence: 84%

Over-Expressing Prohibitin (PHB) in Neuronal Cultures Exacerbates Cell Death Following Hydrogen Peroxide and L-Glutamic Acid Induced Injury

Teoh¹,

Boulos²,

Chieng³

et al. 2014

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Using proteomics, previous work in our laboratory identified five mitochondrial related proteins [citrate synthase (CS), glucose-regulated protein 75 (GRP75), heat shock protein 60 (HSP60), prohibitin (PHB), voltage-dependent anion channel 1 (VDAC1)] to be differentially expressed in primary cortical neuronal cultures following preconditioning treatments [1] [2]. To investigate a protective or damaging role of these five proteins in neurons, we used RNAi constructs to knockdown and adenoviral vectors to over-express the proteins in cortical neuronal cultures prior to exposure to three ischemia-related injury models: excitotoxicity (L-glutamic acid), oxidative stress (hydrogen peroxide) and in vitro ischemia (oxygen-glucose deprivation). We observed that downregulating these mitochondrial proteins had no effect on neuronal viability, in any injury model. By contrast, over-expression of PHB exacerbated cell death in the hydrogen peroxide and L-glutamic acid injury models. These findings indicate that PHB plays a neurodamaging role following oxidative and excitotoxic stress and suggests that the protein is a potential therapeutic target for the design of drugs to limit neuronal death following cerebral ischemia and other forms of brain injury.

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Section: Discussioncontrasting

confidence: 84%

Over-Expressing Prohibitin (PHB) in Neuronal Cultures Exacerbates Cell Death Following Hydrogen Peroxide and L-Glutamic Acid Induced Injury

Teoh¹,

Boulos²,

Chieng³

et al. 2014

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“…Of note, inhibition of the MPT by drugs that might interact with cyclophilin-D (e.g. cyclosporine A; Li et al, 2000;Waldmeier et al, 2003) or antibodies to MPT pore elements (Perez Velazquez et al, 2003) provide ischemic neuroprotection with reduced mitochondrial swelling and inhibition of cytochrome c release. Cumulatively, MPT provides a convergence between various oxidative and anti-oxidative forces that are likely to have major impact on ischemic outcome.…”

Section: Mitochondrial Permeability Transition Inhibitorsmentioning

confidence: 99%

Oxidants, antioxidants and the ischemic brain

Warner

Sheng

Batinić‐Haberle

2004

Journal of Experimental Biology

540

362

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SUMMARY Despite numerous defenses, the brain is vulnerable to oxidative stress resulting from ischemia/reperfusion. Excitotoxic stimulation of superoxide and nitric oxide production leads to formation of highly reactive products,including peroxynitrite and hydroxyl radical, which are capable of damaging lipids, proteins and DNA. Use of transgenic mutants and selective pharmacological antioxidants has greatly increased understanding of the complex interplay between substrate deprivation and ischemic outcome. Recent evidence that reactive oxygen/nitrogen species play a critical role in initiation of apoptosis, mitochondrial permeability transition and poly(ADP-ribose) polymerase activation provides additional mechanisms for oxidative damage and new targets for post-ischemic therapeutic intervention. Because oxidative stress involves multiple post-ischemic cascades leading to cell death, effective prevention/treatment of ischemic brain injury is likely to require intervention at multiple effect sites.

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“…Thus the F(ab)(2) fragments of anti-porin antibodies can penetrate living cells and reduce Ca 2+ -induced mitochondrial swelling in brain slice cultures exposed to excitotoxic and ischemic events [179]. However, further investigations are needed to evaluate the therapeutic potential of anti-porin antibodies.…”

Section: Fig (4) Mitochondrial Targets Against Oxidative Ischemic Dmentioning

confidence: 99%

Mitochondria: A Target for Neuroprotective Interventions in Cerebral Ischemia-Reperfusion

Morin¹,

Simon

2006

CPD

195

109

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Evidence obtained over the past two decades shows that reactive oxygen species (ROS) are involved in brain lesions, including those due to cerebral ischemia-reperfusion. The mitochondria are the primary intracellular source of ROS, as they generate huge numbers of oxidative-reduction reactions and use massive amounts of oxygen. When anoxia is followed promptly by reperfusion, the resulting increase in oxygen supply leads to overproduction of ROS. In ischemic tissues, numerous studies have established a direct role for ROS in oxidative damage to lipids, proteins, and nucleic acids. Thus, mitochondria are both the initiator and the first target of oxidative stress. Mitochondrial damage can lead to cell death, given the role for mitochondria in energy metabolism and calcium homeostasis, as well as the ability of mitochondria to release pro-apoptotic factors such as cytochrome C and apoptosis-inducing factor (AIF). This review discusses possible mitochondrion-targeted strategies for preventing ROS-induced injury during reperfusion. The sequence of events that follow oxidative damage provides the outline for the review: thus, we will discuss protection of oxidative phosphorylation, mitochondrial membrane integrity and fluidity, and antioxidant or mild-uncoupling strategies for diminishing ROS production. Among mechanisms of action, we will describe the modulation of mitochondrial permeability transition pore (MPTP) opening, which may not only operate as a physiological Ca(2+) release mechanism, but also contribute to mitochondrial deenergization, release of pro-apoptotic proteins, and protection by ischemic preconditioning (IPC). Finally, we will review genetic strategies for controlling apoptotic protein expression, stimulating mitochondrial oxidative defences, and increasing mitochondrial proliferation.

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Anti-Porin Antibodies Prevent Excitotoxic and Ischemic Damage to Brain Tissue

Cited by 9 publications

References 75 publications

Over-Expressing Prohibitin (PHB) in Neuronal Cultures Exacerbates Cell Death Following Hydrogen Peroxide and L-Glutamic Acid Induced Injury

Over-Expressing Prohibitin (PHB) in Neuronal Cultures Exacerbates Cell Death Following Hydrogen Peroxide and L-Glutamic Acid Induced Injury

Oxidants, antioxidants and the ischemic brain

Mitochondria: A Target for Neuroprotective Interventions in Cerebral Ischemia-Reperfusion

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