Review: Oxidative Stress And ExcitoToxicity: A Therapeutic Issue In Multiple Sclerosis?
There is increasing evidence that Multiple Sclerosis (MS) is not only characterized by Immune mediated inflammatory reactions but also by NeuroDegenerative processes.
In NeuroDegenerative Diseases, Neuronal and Axonal Loss is mediated by Oxidative Stress and ExcitoToxicity which constitute a final common toxic pathway.
Importantly, Peroxynitrite is the key mediator of those two intertwined pathomechanisms.
In MS, Peroxynitrite is consistently associated with active lesions and produces highly toxic Nitrating and Oxidizing radical species that alter Lipid, Protein, DNA and Mitochondrial structures and functions.
During the Remitting phase, Peroxynitrite participates to Neuron and Oligodendrocyte damage in association with inflammatory processes.
During the chronic phase, Peroxynitrite contributes to self-perpetuating mechanisms responsible for disease progression.
Neutralization of Oxidative Stress and ExcitoToxicity, and in particular of Peroxynitrite derived free radicals, might represent a therapeutic approach to provide NeuroProtection in MS.
Multiple Sclerosis 2008; 14: 22-34. http://msj.sagepub.com.
Mitochondrial Dysfunction And Dendritic Beading During Neuronal Toxicity
Greenwood SM, Mizielinska SM, Frenguelli BG, Harvey J, Connolly CN
J Biol Chem 2007 Sep 7;282(36):26235-44
University of Dundee, Dundee DD19SY, Ninewells Medical School, NeuroSciences Institute, Scotland, United Kingdom
Mitochondrial Dysfunction (depolarization and structural collapse), cytosolic ATP depletion, and Neuritic Beading are early hallmarks of Neuronal toxicity induced in a variety of pathological conditions.
We show that, following global exposure to Glutamate, Mitochondrial changes are spatially and temporally coincident with Dendritic Bead formation.
During Oxygen-Glucose deprivation, Mitochondrial depolarization precedes Mitochondrial collapse, which in turn is followed by Dendritic Beading.
These events travel as a wave of activity from distal Dendrites toward the Neuronal Cell Body.
Despite the SpatioTemporal relationship between dysfunctional Mitochondria and Dendritic Beads, Mitochondrial depolarization and cytoplasmic ATP depletion do not trigger these events.
However, Mitochondrial Dysfunction increases Neuronal vulnerability to these morphological changes during normal physiological activity.
Our findings support a mechanism whereby, during Glutamate ExcitoToxicity, Ca2+ influx leads to Mitochondrial depolarization, whereas Na+ influx leads to an unsustainable increase in ATP demand (Na+, K+-ATPase activity).
This leads to a drop in ATP levels, an accumulation of IntraCellular Na+ Ions, and the subsequent influx of water, leading to MicroTubule depolymerization, Mitochondrial collapse, and Dendritic Beading.
Following the removal of a Glutamate challenge, Dendritic recovery is dependent upon the integrity of the Mitochondrial membrane potential, but not on a resumption of ATP synthesis or Na+,K+-ATPase activity.
Thus, Dendritic recovery is not a passive reversal of the events that induce Dendritic Beading.
These findings suggest that the degree of Calcium influx and Mitochondrial depolarization inflicted by a NeuroToxic challenge, determines the ability of the Neuron to recover its normal morphology.
Cyclophilin D Inactivation Protects Axons In Experimental Autoimmune Encephalomyelitis, An Animal Model Of Multiple Sclerosis
Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, Yu X, Fowlkes J, Rahder M, Stem K, Bernardi P, Bourdette D
Proc Natl Acad Sci USA 2007 May 1;104(18):7558-63
Oregon Health and Science University, Vollum Institute, Portland, OR 97239, USA
Multiple Sclerosis (MS) is the leading cause of Neurological Disability in young adults, affecting some two million people worldwide.
Traditionally, MS has been considered a chronic, inflammatory disorder of the Central White Matter in which ensuing DeMyelination results in physical disability [Frohman EM, Racke MK, Raine CS (2006) N Engl J Med 354:942-955].
More recently, MS has become increasingly viewed as a NeuroDegenerative Disorder in which Neuronal Loss, Axonal Injury, and Atrophy of the CNS lead to permanent Neurological and clinical disability.
Although Axonal pathology and loss in MS has been recognized for >100 years, very little is known about the underlying molecular mechanisms.
Progressive Axonal Loss in MS may stem from a cascade of Ionic imbalances initiated by inflammation, leading to Mitochondrial Dysfunction and energetic deficits that result in Mitochondrial and cellular Ca2+ overload.
In a murine disease model, Experimental Autoimmune Encephalomyelitis (EAE) mice lacking Cyclophilin D (CyPD), a key regulator of the Mitochondrial Permeability Transition Pore (PTP), developed EAE.
But unlike WT mice, they partially recovered. Examination of the Spinal Cords of CyPD-knockout mice revealed a striking preservation of Axons, despite a similar extent of inflammation.
Furthermore, Neurons prepared from CyPD-knockout animals were resistant to Reactive Oxygen and Nitrogen species thought to mediate Axonal Damage in EAE and MS, and Brain Mitochondria lacking CyPD sequestered substantially higher levels of Ca2+.
Our results directly implicate pathological activation of the Mitochondrial PTP in the Axonal Damage occurring during MS and identify CyPD, as well as the PTP, as a potential target for MS MS NeuroProtective therapies.
Peroxynitrite-Induced Oligodendrocyte Toxicity Is Not Dependent On Poly(ADP-ribose) Polymerase Activation
Scott GS, Virág L, Szabó C, Hooper DC
Glia 2003 Jan 15;41(2):105-16
Thomas Jefferson University, Department of MicroBiology and Immunology, Philadelphia, Pennsylvania 19107, USA
Oligodendrocyte loss is a characteristic feature of several CNS disorders, including Multiple Sclerosis (MS) and Spinal Cord Injury.
However, the mechanisms responsible for Oligodendrocyte destruction remain undefined. As recent studies have implicated Peroxynitrite in the pathogenesis of both Spinal Cord Injury and MS.
We have examined whether Peroxynitrite may mediate at least some of the Oligodendrocyte damage and DeMyelination observed in these conditions. Primary rat Oligodendrocytes were exposed to authentic Peroxynitrite in vitro and assessed for CytoToxicity.
Mitochondrial function, measured by the reduction of MTT to formazan, and Mitochondrial membrane potential were used as indicators of cell viability.
Cell death was quantitated by measuring either the release of Lactate Dehydrogenase from, or the uptake of Propidium Iodide into, damaged and dying cells.
Peroxynitrite dose-dependently reduced the viability of primary Oligodendrocytes and induced cell death. Furthermore, Peroxynitrite significantly increased DNA strand breakage and the activity of poly(ADP-ribose) polymerase (PARP) in Oligodendrocyte cultures.
To identify whether PARP activation plays a role in Peroxynitrite-induced Oligodendrocyte toxicity, we examined the effects of the PARP inhibitors 3-AminoBenzamide (3AB) and 5-Iodo-6-Amino-1,2-Benzopyrone (INH(2)BP) on Mitochondrial function and cell death in Oligodendrocytes.
The presence of 3AB and INH(2)BP did not protect Oligodendrocytes from Peroxynitrite-induced CytoToxicity. However, both compounds significantly reduced PARP activity in these cells.
Primary Oligodendrocytes generated from PARP-deficient mice were also highly susceptible to Peroxynitrite-induced cell death. Therefore, our results show that Peroxynitrite exerts CytoToxic effects on Oligodendrocytes in vitro independently of PARP activation.
Copyright 2003 Wiley-Liss, Inc.