Nitric Oxide and Cellular Stress Response in Brain Aging and Neurodegenerative Disorders: the Role of Vitagenes
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in vivo 18: 245-268 (2004) Review Nitric Oxide and Cellular Stress Response in Brain Aging and Neurodegenerative Disorders: The Role of Vitagenes VITTORIO CALABRESE1, DEBRA BOYD-KIMBALL2, GIOVANNI SCAPAGNINI1,3 and D. ALLAN BUTTERFIELD2 1Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of Medicine, University of Catania, Catania, Italy; 2Department of Chemistry, Center of Membrane Sciences and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, U.S.A.; 3CNR, University of Catania, Catania, Italy Abstract. Nitric oxide and other reactive nitrogen species appear increased nitrogen monoxide formation and nitrosative stress. It to play crucial roles in the brain such as neuromodulation, is now well documented that NO and its toxic metabolite, neurotransmission and synaptic plasticity, but are also involved in peroxynitrite, can inhibit components of the mitochondrial pathological processes such as neurodegeneration and respiratory chain leading to cellular energy deficiency and, neuroinflammation. Acute and chronic inflammation result in eventually, to cell death. Within the brain, the susceptibility of different brain cell types to NO and peroxynitrite exposure may be dependent on factors such as the intracellular reduced glutathione and cellular stress resistance signal pathways. Thus Abbreviations: Alzheimer’s disease: (AD); Parkinson’s disease: (PD); amyotrophic lateral sclerosis: (ALS); Multiple sclerosis: (MS); neurons, in contrast to astrocytes, appear particularly vulnerable Huntington's disease: (HD); Huntingtin: (Htt); electron transport to the effect of nitrosative stress. Evidence is now available to chain: (ETC); activator protein-1: (AP-1); stress-activated protein support this scenario for neurological disorders such as kinase (SAPK); c-jun N-terminal kinase: (JNK); nuclear factor kappa- Alzheimer’s disease, amyothrophic lateral sclerosis, Parkinson’s B: (NFkB); heat shock protein: (HSP); mitogen-activated protein disease, multiple sclerosis and Huntington’s disease, but also in kinase: (MAPK); signal transducer and transcription activator: the brain damage following ischemia and reperfusion, Down’s (STAT); tumor necrosis factor; (TNF); janus kinase: (JAK); N- syndrome and mitochondrial encephalopathies. To survive methyl-D-aspartate: (NMDA); substantia nigra: (SN); Central different types of injuries, brain cells have evolved integrated nervous system: (CNS); phospholipase A2: (PLA)2; N-ethylmaleimide: (NEM); reduced glutathione: (GSH); oxidized glutathione: (GSSG); responses, the so-called longevity assurance processes, composed N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: (MPP+); reactive of several genes termed vitagenes and including, among others, oxygen species: (ROS); superoxide dismutase: (SOD); glutathione members of the HSP system, such as HSP70 and HSP32, to peroxidase: (GPX); cyclo-oxygenase: (COX-2); intraneuronal fibrillary detect and control diverse forms of stress. In particular, HSP32, tangles: (NFT); amyloid beta-peptide: (A‚); advanced glycosylation also known as heme oxygenase-1 (HO-1), has received end products: (AGEs); nitric oxide synthase: (NOS). considerable attention, as it has been recently demonstrated that Correspondence to: Prof. D. Allan Butterfield, Department of HO-1 induction, by generating the vasoactive molecule carbon Chemistry, Center of Membrane Sciences and Sanders-Brown monoxide and the potent antioxidant bilirubin, could represent a Center on Aging, 121 Chemistry-Physics Building, University of protective system potentially active against brain oxidative injury. Kentucky, Lexington, KY 40506-0055 U.S.A. Tel: 859-257-3184, Fax: Increasing evidence suggests that the HO-1 gene is redox- 859-257-5876, e-mail: [email protected] or Prof. Vittorio Calabrese, regulated and its expression appears closely related to conditions Section of Biochemistry and Molecular Biology, Department of of oxidative and nitrosative stress. An amount of experimental Chemistry, Faculty of Medicine, University of Catania, Viale Andrea evidence indicates that increased rate of free radical generation Doria 6-95100 Catania, Italy. Tel: 0039-095-738-4067, Fax: 0039-095- 580138, e-mail: [email protected] and decreased efficiency of the reparative/degradative mechanisms, such as proteolysis, are factors that primarily Key Words: Neurodegenerative disorders, NOS, heat shock contribute to age-related elevation in the level of oxidative stress proteins, nitrosative stress, vitagenes. and brain damage. Given the broad cytoprotective properties of 0258-851X/2004 $2.00+.40 245 in vivo 18: 245-268 (2004) the heat shock response there is now strong interest in discovering thiols is crucial in determining the sensitivity of cells to and developing pharmacological agents capable of inducing such oxidative and nitrosative stress (4). Nitric oxide (NO) a response. These findings have led to new perspectives in derived from neuronal nitric oxide synthase (nNOS) and medicine and pharmacology, as molecules inducing this defense endothelial nitric oxide synthase appears to have an mechanism appear to be possible candidates for novel, important role in neural signaling and immunomodulation, cytoprotective strategies. Particularly, manipulation of as well as in the regulation of mitochondrial respiratory endogenous cellular defense mechanisms such as the heat shock chain complex IV activity. The activity of inducible nitric response, through nutritional antioxidants or pharmacological oxide synthase (iNOS) is much higher than nNOS or eNOS, compounds, represents an innovative approach to therapeutic and the induction of iNOS, producing greater amounts of intervention in diseases causing tissue damage, such as NO than nNOS or eNOS, is usually associated with cellular neurodegeneration. Consistent with this notion, maintenance or pathology. The actions of NO can be either direct, resulting recovery of the activity of vitagenes may possibly delay the aging from reactions between NO and specific biological process and decrease the occurrence of age-related diseases with molecules, or indirect, resulting from reactions of NO- resulting prolongation of a healthy life span. derived reactive nitrogen species; for instance, the reaction of NO with superoxide produces the peroxynitrite anion and Perturbation of the cellular oxidant/antioxidant balance has represents an important pathway of NO reactivity. been suggested to be involved in the neuropathogenesis of Peroxynitrite is a powerful oxidant and can nitrate aromatic several disease states, including stroke, Parkinson’s disease amino acid residues such as tyrosine to form nitrotyrosine. (PD), Alzheimer’s disease (AD), as well as "normal" Nitration to form 3-nitrotyrosine can occur on either free or physiological aging (1). Reactive oxygen species (ROS) are protein-bound tyrosine. Since the half-life of peroxynitrite constantly produced in the course of aerobic metabolism, at physiological pH is short the detection of 3-nitrotyrosine and in normal conditions there is a steady-state balance in tissues is often used as a biological marker of between prooxidants and antioxidants. Most of the reactive peroxynitrite generation in vivo. Not only is 3-nitrotyrosine species produced by healthy cells results from "leakage" or a marker for peroxynitrite production, but it appears that short circuiting of electrons at several specific locations the nitration of specific proteins by peroxynitrite may be within the cell, which then become sources of free radical relevant to brain pathophysiology (3, 5). production. These include: the mitochondrial respiratory In contrast to the conventional idea that reactive species chain, the enzyme xanthine oxidase and, to a lesser extent, serve as a trigger for oxidative damage of biological arachidonic acid metabolism and autooxidation of structures, we now know that low physiologically relevant catecholamines or hemoproteins. However, when the rate concentration of oxidants can regulate a variety of key of free radical generation exceeds the capacity of molecular mechanisms. In light of this, the significance of antioxidant defenses, oxidative stress ensues causing oxidants in various aspects of biology and medicine needs extensive damage to DNA, proteins and lipids (2). to be revisited. Oxidants may function as cellular The brain has a large potential oxidative capacity (3) due to messengers that regulate a variety of signal transduction the high level of tissue oxygen consumption. However, the pathways (6). Mild oxidative stress in fact has been shown ability of the brain to combact oxidative stress is limited for the to modify the expression of most important antioxidant following anatomical, physiological and biochemical reasons: enzymes as well as to enhance expression and DNA binding a) high content of easily oxidizable substrates, such as of numerous transcription factors, including AP-1, fos, jun, polyunsaturated fatty acids and catecholamines; b) the myc, erg-1, SAPK, nuclear factor-kB (NFkB), heat shock relatively low levels of antioxidants such as glutathione and factor (HSF) and NF-E2-related factors 2 (Nrf2) (6,7). vitamin E and antioxidant enzymes (such as GSH peroxidase, To adapt to environmental changes and survive different catalase and superoxide dismutase); c) the endogenous types of injuries, eukaryotic cells have evolved networks of generation of reactive oxygen free radicals via several specific different responses which detect and control diverse forms reactions;