Chronic consumption of ethanol has a damaging effect in various organs and metabolic functions, including liver, kidney, heart, pancreas, and brain (Sun and Sun, 2001; Bezerra Rde et al., 2005). Additionally, it has been shown that both the acute and chronic ethanol intake induce alteration in voltage-gated channels causing behavioral and electrophysiological changes in the brain (Little, 1999). In the last few years, the effect of ethanol in the electrophysiological phenomenon, known as cortical spreading depression (CSD), has been widely assessed (Sonn and Mayevsky, 2001; Bezerra Rde et al., 2005; Abadie-Guedes et al., 2008) as an important model to predict the damaging effects of ethanol in both young and aged brains.Fil: Barreto, George E.. Pontificia Universidad Javeriana; ColombiaFil: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); ArgentinaFil: Cabezas, Ricardo. Pontificia Universidad Javeriana; Colombi

Barreto, George E.

Cabezas, Ricardo

Capani, Francisco

Frontiers in Aging Neuroscience

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George E. Barreto

Francisco Capani

Ricardo Cabezas

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Cortical spreading depression and mitochondrial dysfunction with aging: lessons from ethanol abuse

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OPINION ARTICLEpublished: 10        June 2014doi: 10.3389/fnagi.2014.00117Cortical spreading depression and mitochondrialdysfunction with aging: lessons from ethanol abuseGeorge E. Barreto1*, Francisco Capani2 and Ricardo Cabezas11 Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia2 Laboratorio de Citoarquitectura y Plasticidad Neuronal, Facultad de Medicina, Instituto de Investigaciones Cardiológicas Prof. Dr. Alberto C. Taquini (ININCA),UBA-CONICET, Buenos Aires, Argentina*Correspondence: gsampaio@javeriana.edu.coEdited by:Merce Pallas, University of Barcelona, SpainReviewed by:Enrico Sanna, University of Cagliari, ItalyRubem C. A. Guedes, Universidade Federal de Pernambuco, BrazilKeywords: cortical spreading depression, ethanol, mitochondria dysfunction, antioxidants, agingChronic consumption of ethanol has adamaging effect in various organs andmetabolic functions, including liver, kid-ney, heart, pancreas, and brain (Sun andSun, 2001; Bezerra Rde et al., 2005).Additionally, it has been shown that boththe acute and chronic ethanol intakeinduce alteration in voltage-gated chan-nels causing behavioral and electrophysio-logical changes in the brain (Little, 1999).In the last few years, the effect of ethanolin the electrophysiological phenomenon,known as cortical spreading depression(CSD), has been widely assessed (Sonnand Mayevsky, 2001; Bezerra Rde et al.,2005; Abadie-Guedes et al., 2008) as animportant model to predict the damagingeffects of ethanol in both young and agedbrains.Cortical spreading depression is a neu-ronal and glial depolarization wave in graymatter, which is thought to be associatedas an upstream event in migraine withaura, spontaneous intracerebral hemor-rhage, ischemic injury and brain trauma(Zhou et al., 2010; Dreier, 2011). Thisphenomenon has a duration of approxi-mately 1 min and very slow propagation(2–5 mm/min) when compared to actionpotentials, resulting in a suppression ofelectrical activity and disruption of ionhomeostasis (Bennett et al., 2008; Seideland Shuttleworth, 2011). This depolar-ization occurs when the extracellular K+concentrations increase above a thresh-old of 40 mM, causing the CSD wavepropagation into adjacent cells. CSD alsorequires the activation of the N-methyl-D-aspartate (NMDA) subtype of glutamatereceptor, which facilitates the spread of thedepolarization wave (Eikermann-Haerterand Ayata, 2010).There are experimental evidences tosuggest that various factors influencethe brain CSD propagation, includingpharmacological substances, age, ethanolabuse and the insufficient ingestion ofantioxidants (Abadie-Guedes et al., 2008).To support this idea, previous reporthas shown that acute ethanol ingestionimpairs the CSD propagation when com-pared to chronic administration of 7, ormore days, in which this phenomenon issomehow stimulated (Bezerra Rde et al.,2005). Furthermore, it was previouslyreported that ethanol-treated rats hadalterations in the NADH oxidation cycleand a decrease in energy production andCSD wave frequency (Sonn and Mayevsky,2001). Acute ethanol administration hasbeen also associated with the inhibition ofthe Na+-K+-ATPase pump function, theformation of free oxygen radicals and CSDregulation (Sonn and Mayevsky, 2001). Inthis aspect, ethanol increases lipid per-oxidation in the brain and the serumNO (nitric oxide) levels, probably dueto the activation of the inducible nitricoxide synthase (iNOS) by cytokines (Zimaet al., 2001). Chronic ethanol adminis-tration affects the antioxidant defenses ofthe brain by reducing the levels of glu-tathione, peroxidase, α -tocopherol, glu-tathione reductase and catalase (BezerraRde et al., 2005), and the aged brain is par-ticularly affected by this reduced antiox-idant scavenging system (Reiter, 1995).Indeed, it is possible that cytoplasmiccalcium levels may also be implicated inCSD deflagration (Torrente et al., 2014b).Altogether, these findings suggest thatthere are multiple mechanisms by whichethanol may damage the brain (Figure 1).Although one of the main mechanismsof ethanol-induced brain damage is dueto an augmented production of reactiveoxygen species (ROS), thus leading toincreased CSD propagation, this statementhas not been experimentally addressed.Most studies on CSD focused on the elec-trophysiological effects of ethanol abuse,and their reversion by some protectivemolecules, such as astaxanthin (Abadie-Guedes et al., 2008, 2012). To address thisconcern, it is important to point that (i)ethanol facilitates P450 2E1 activity, whichmetabolizes this compound and gener-ates ROS in the process; and (ii) ethanolincreases the levels of free iron in thecell, which also can promote ROS genera-tion. It is possible that most antioxidantsmay reverse, scavenge, or even impairthe production of free radicals and exertprotection through this pathway. Ethanolaffects the immune system in aged mice,suggesting that this might be one the mainmechanisms by which ethanol inducesneurodegeneration in aged brains (Drewand Kane, 2013; Kane et al., 2014).Interestingly, astrocytes have beenshown to be more resistant than neu-rons during ethanol-induced oxidativestress because of their greater contentof glutathione (GSH) and other antiox-idant enzymes (Watts et al., 2005; Barretoet al., 2011), and these cells may play animportant role in CSD (Torrente et al.,Frontiers in Aging Neuroscience www.frontiersin.org June 2014 | Volume 6 | Article 117 | 1AGING NEUROSCIENCEBarreto et al. CSD and ethanol with agingFIGURE 1 | Ethanol effects on CSD related processes. Ethanoladministration induces the inhibition of Na+-K+ -ATPase pump, depleting theATP contents of the cell, and causing the generation of ROS and lipidperoxidation. Both chronic and acute administration of ethanol has impairingeffects in CSD velocities, which in turn may reflect important alterations onthe bioenergetic metabolism. Additionally, ethanol increases the expressionof iNOS and the formation of NO, decreases the levels of antioxidantenzymes, like glutathione reductase and catalase, and promotes theactivation of GABA receptor related responses. The administration ofastaxanthin counteracts the effects induced by ethanol in CSD velocities.2014a). On the other hand, the disrup-tion of astrocyte oxidative metabolism,which results in ATP levels decline, hasbeen shown to increase the rate of spread-ing depression in rat cortex (Largo et al.,1997; Seidel and Shuttleworth, 2011),suggesting that metabolic alterations ofastrocytes are an important regulatorof CSD events, especially during nor-mal aging process (Farkas et al., 2011;Paradies et al., 2013; Yin et al., 2014). ATPdepletion is likely to occur due to the oxi-dation of ethanol to acetaldehyde catalyzedby alcohol/dehydrogenase containing thecoenzyme NAD+. The acetaldehyde is fur-ther oxidized to acetic acid and finally CO2and water through the citric acid cycle. Anumber of metabolic effects from ethanolare directly linked to the production of anexcess of both NADH and acetaldehyde.In this context, more NADH will dislocatethe equilibrium of converting glucose topiruvate for energy production toward aoverproduction of lactate and malate frompiruvate. The increased accumulation ofacetaldehyde by reduced conversion of thisproduct into acetic acid—both processesimpair mitochondrial functions and ener-getic metabolism—results in decreasedATP production. It is important to pointthat brain metabolism in the aged brain issomehow impaired, therefore the damag-ing effects of CSD are augmented (Farkaset al., 2011; Batista-De-Oliveira et al.,2012).Following a cortical spreading depres-sion event, metabolic recovery is compro-mised, as glucose and glycogen levels aresignificantly decreased and lactate levelsare found increased (anaerobic shuttle),thus leading to intense depolarization andcell death (Selman et al., 2004). In thiscontext, we hypothesize that aging influ-ences brain electrophysiological function-ing due to reduced metabolic shuttle andantioxidant defense, and the impairmentof both energy metabolism and redoxhomeostasis are a hallmark of brain aging(Yin et al., 2014). These observations areparticularly seen in older people withalcoholism problems. A previous studyreported that brain tissue loss was foundincreased in older subjects with alcoholismcompared to younger subjects with alco-holism (Oscar-Berman et al., 1997), andthis may accelerate normal aging processor cause premature aging of the brain.Importantly, ethanol was shown to impairvasodilatation enzymes such as nNOS(neuronal nitric oxide synthase) and eNOSFrontiers in Aging Neuroscience www.frontiersin.org June 2014 | Volume 6 | Article 117 | 2Barreto et al. CSD and ethanol with aging(endothelial nitric oxide synthase) by theaugmentation of ROS, and this was asso-ciated with an increase in ischemic braindamage in elder individuals (Sun et al.,2006).To counteract this damaging effectof ethanol on aged brain, and follow-ing CSD, different antioxidant moleculesand enzymes, such as α-tocopherol, ascor-bic acid, peroxiredoxin, and astaxan-thin are shown to be neuroprotectiveagainst ethanol intake in animal models(Bezerra Rde et al., 2005; Lee et al., 2010;Zhu et al., 2012). The carotenoid astax-anthin (3,3′-dihydroxy-β,β-carotene-4,4′-dione) has important metabolic functions,including its conversion to vitamin A,enhancement of immune response, inhibi-tion of NO and lipopolysaccaride (LPS)-induced inflammation, scavenging actionon reactive oxygen species, and protectionof gastric mucosa against ethanol-inducedinjuries (Kim et al., 2005; Lee et al.,2010). Astaxanthin was also shown toprotect against induced cerebral ischemiain rats by the inhibition on iNOS andinduce the expression of Hsp32 andHsp70, demonstrating a decrease in oxida-tive stress without affecting cell viability.This information supports the idea of anoxidative mechanism by which astaxan-thin may be exerting a protective effecton ethanol induced damage. On this per-spective, new findings on the antioxidanteffects of astaxanthin and their relation-ship with CSD were previously reported(Abadie-Guedes et al., 2012). In this study,the antagonistic effects of acute ethanolconsumption on CSD propagation in twogroups of rats with different ages wereassessed. Their main results showed thatCSD outcome was counteracted by astax-anthin administration. Age of animals andtime of ethanol/astaxantin administrationare the key features, and age related effectsof ethanol in the brain should be fur-ther addressed in additional experimentsrelated with ROS production in bothbrain and blood of the treated animals,as well as the expression of antioxidantenzymes such as iNOs or SOD (superox-ide dismutase). In this point of view, somehypotheses must be raised: (i) Perhaps, theantioxidant properties of astaxanthin onthe scavenging of ROS could explain thereversion of ethanol effect on CSD veloci-ties; and (ii) alternatively, it is possible thatethanol action on CSD involves an inter-action with the GABA-chloride ion chan-nels and the NMDA receptors, causing asuppression of nerve cell activity, throughionic modulation (Sonn and Mayevsky,2001; Criswell et al., 2003). Whether ornot this relationship between astaxanthinand the GABA is clear, this is a concernthat deserves further attention. Moreover,it is important to address the possible neu-roprotective effects of other antioxidantson the modulation of CSD in the settingof a pathophysiological condition, as ismigraine with aura, stroke or brain injury,and also in the normal aging process.REFERENCESAbadie-Guedes, R., Guedes, R. C., and Bezerra, R.S. (2012). The impairing effect of acute ethanolon spreading depression is antagonized by astax-anthin in rats of 2 young-adult ages. Alcohol.Clin. Exp. Res. 36, 1563–1567. doi: 10.1111/j.1530-0277.2012.01766.xAbadie-Guedes, R., Santos, S. D., Cahu, T. B.,Guedes, R. C., and De Souza Bezerra, R.(2008). Dose-dependent effects of astaxanthinon cortical spreading depression in chroni-cally ethanol-treated adult rats. Alcohol. Clin.Exp. Res. 32, 1417–1421. doi: 10.1111/j.1530-0277.2008.00710.xBarreto, G. E., Gonzalez, J., Torres, Y., andMorales, L. (2011). Astrocytic-neuronalcrosstalk: implications for neuroprotectionfrom brain injury. Neurosci. Res. 71, 107–113. doi:10.1016/j.neures.2011.06.004Batista-De-Oliveira, M., Lopes, A. A., Mendes-Da-Silva, R. F., and Guedes, R. C. (2012).Aging-dependent brain electrophysiologicaleffects in rats after distinct lactation conditions,and treadmill exercise: a spreading depres-sion analysis. Exp. Gerontol. 47, 452–457. doi:10.1016/j.exger.2012.03.016Bennett, M. R., Farnell, L., and Gibson, W. G.(2008). A quantitative model of cortical spreadingdepression due to purinergic and gap-junctiontransmission in astrocyte networks. Biophys.J. 95, 5648–5660. doi: 10.1529/biophysj.108.137190Bezerra Rde, S., Abadie-Guedes, R., Melo, F. R., Paiva,A. M., Amancio-Dos-Santos, A., and Guedes, R. C.(2005). Shrimp carotenoids protect the developingrat cerebral cortex against the effects of ethanol oncortical spreading depression. Neurosci. Lett. 391,51–55. doi: 10.1016/j.neulet.2005.08.040Criswell, H. E., Ming, Z., Griffith, B. L., andBreese, G. R. (2003). Comparison of effect ofof ethanol on N-methyl-D-aspartate- and GABA-gated currents from acutely dissociated neurons:absence of regional differences in sensitivity toethanol. J. Pharmacol. Exp. Ther. 304, 192–199.doi: 10.1124/jpet.102.041590Dreier, J. P. (2011). The role of spreading depression,spreading depolarization and spreading ischemiain neurological disease. Nat. Med. 17, 439–447.doi: 10.1038/nm.2333nm.2333Drew, P. D., and Kane, C. J. (2013). “Neuroimmunemechanisms of glia and their interplay withalcohol exposure across the lifespan,” in Neural-Immune Interactions in Brain Function andAlcohol Related Disorders, ed C. Cui (NewYork, NY: Springer Science + Business Media),359–386.Eikermann-Haerter, K., and Ayata, C. (2010). Corticalspreading depression and migraine. Curr. Neurol.Neurosci. Rep. 10, 167–173. doi: 10.1007/s11910-010-0099-1Farkas, E., Obrenovitch, T. P., Institoris, A., andBari, F. (2011). Effects of early aging andcerebral hypoperfusion on spreading depressionin rats. Neurobiol. Aging 32, 1707–1715. doi:10.1016/j.neurobiolaging.2009.10.002Kane, C. J., Phelan, K. D., Douglas, J. C., Wagoner,G., Johnson, J. W., Xu, J., et al. (2014). Effectsof ethanol on immune response in the brain:region-specific changes in adolescent versus adultmice. Alcohol. Clin. Exp. Res. 38, 384–391. doi:10.1111/acer.12244Kim, J. H., Choi, S. K., Choi, S. Y., Kim, H. K.,and Chang, H. I. (2005). Suppressive effect ofastaxanthin isolated from the Xanthophyllomycesdendrorhous mutant on ethanol-induced gas-tric mucosal injury in rats. Biosci. Biotechnol.Biochem. 69, 1300–1305. doi: 10.1271/bbb.69.1300Largo, C., Ibarz, J. M., and Herreras, O. (1997). Effectsof the gliotoxin fluorocitrate on spreading depres-sion and glial membrane potential in rat brain insitu. J. Neurophysiol. 78, 295–307.Lee, D. H., Lee, Y. J., and Kwon, K. H. (2010).Neuroprotective effects of astaxanthin in oxygen-glucose deprivation in sh-sy5y cells and globalcerebral ischemia in rat. J. Clin. Biochem. Nutr. 47,121–129. doi: 10.3164/jcbn.10-29Little, H. J. (1999). The contribution of electrophysi-ology to knowledge of the acute and chronic effectsof ethanol. Pharmacol. Ther. 84, 333–353. doi:10.1016/S0163-7258(99)00040-6Oscar-Berman, M., Shagrin, B., Evert, D. L., andEpstein, C. (1997). Impairments of brain andbehavior: the neurological effects of alcohol.Alcohol Health Res. World 21, 65–75.Paradies, G., Paradies, V., Ruggiero, F. M., andPetrosillo, G. (2013). Changes in the mitochon-drial permeability transition pore in aging and age-associated diseases. Mech. Ageing Dev. 134, 1–9.doi: 10.1016/j.mad.2012.12.006Reiter, R. J. (1995). Oxidative processes and antioxida-tive defense mechanisms in the aging brain. FASEBJ. 9, 526–533.Seidel, J. L., and Shuttleworth, C. W. (2011).Contribution of astrocyte glycogen stores to pro-gression of spreading depression and related eventsin hippocampal slices. Neuroscience 192, 295–303.doi: 10.1016/j.neuroscience.2011.05.006Selman, W. R., Lust, W. D., Pundik, S., Zhou, Y., andRatcheson, R. A. (2004). Compromised metabolicrecovery following spontaneous spreading depres-sion in the penumbra. Brain Res. 999, 167–174.doi: 10.1016/j.brainres.2003.11.016Sonn, J., and Mayevsky, A. (2001). The effect ofethanol on metabolic, hemodynamic and elec-trical responses to cortical spreading depression.Brain Res. 908, 174–186. doi: 10.1016/S0006-8993(01)02643-9Frontiers in Aging Neuroscience www.frontiersin.org June 2014 | Volume 6 | Article 117 | 3Barreto et al. CSD and ethanol with agingSun, A. Y., and Sun, G. Y. (2001). Ethanol and oxida-tive mechanisms in the brain. J. Biomed. Sci. 8,37–43. doi: 10.1159/000054011Sun, H., Molacek, E., Zheng, H., Fang, Q., Patel, K.P., and Mayhan, W. G. (2006). Alcohol-inducedimpairment of neuronal nitric oxide synthase(nNOS)-dependent dilation of cerebral arterioles:role of NAD(P)H oxidase. J. Mol. Cell. Cardiol. 40,321–328. doi: 10.1016/j.yjmcc.2005.11.004Torrente, D., Cabezas, R., Avila, M. F., Garcia-Segura,L. M., Barreto, G. E., and Guedes, R. C. (2014a).Cortical spreading depression in traumatic braininjuries: is there a role for astrocytes? Neurosci.Lett. 565C, 2–6. doi: 10.1016/j.neulet.2013.12.058Torrente, D., Mendes-Da-Silva, R. F., Lopes, A. A.,Gonzalez, J., Barreto, G. E., and Guedes, R. C.(2014b). Increased calcium influx triggers andaccelerates cortical spreading depression in vivo inmale adult rats. Neurosci. Lett. 558, 87–90. doi:10.1016/j.neulet.2013.11.004Watts, L. T., Rathinam, M. L., Schenker, S., andHenderson, G. I. (2005). Astrocytes protect neu-rons from ethanol-induced oxidative stress andapoptotic death. J. Neurosci. Res. 80, 655–666. doi:10.1002/jnr.20502Yin, F., Boveris, A., and Cadenas, E. (2014).Mitochondrial energy metabolism and redoxsignaling in brain aging and neurodegenera-tion. Antioxid. Redox Signal. 20, 353–371. doi:10.1089/ars.2012.4774Zhou, N., Gordon, G. R., Feighan, D., and Macvicar,B. A. (2010). Transient swelling, acidification, andmitochondrial depolarization occurs in neuronsbut not astrocytes during spreading depression.Cereb. Cortex 20, 2614–2624. doi: 10.1093/cer-cor/bhq018bhq018Zhu, H., Santo, A., and Li, Y. (2012). The antiox-idant enzyme peroxiredoxin and its protectiverole in neurological disorders. Exp. Biol. Med.(Maywood) 237, 143–149. doi: 10.1258/ebm.2011.011152Zima, T., Fialova, L., Mestek, O., Janebova, M.,Crkovska, J., Malbohan, I., et al. (2001). Oxidativestress, metabolism of ethanol and alcohol-related diseases. J. Biomed. Sci. 8, 59–70. doi:10.1159/000054014Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 15 April 2014; accepted: 25 May 2014;published online: 10 June 2014.Citation: Barreto GE, Capani F and Cabezas R (2014)Cortical spreading depression and mitochondrial dys-function with aging: lessons from ethanol abuse. Front.Aging Neurosci. 6:117. doi: 10.3389/fnagi.2014.00117This article was submitted to the journal Frontiers inAging Neuroscience.Copyright © 2014 Barreto, Capani and Cabezas.This is an open-access article distributed under theterms of the Creative Commons Attribution License(CC BY). The use, distribution or reproduction in otherforums is permitted, provided the original author(s) orlicensor are credited and that the original publicationin this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduc-tion is permitted which does not comply with theseterms.Frontiers in Aging Neuroscience www.frontiersin.org June 2014 | Volume 6 | Article 117 | 4

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OPINION ARTICLEpublished: 10        June 2014doi: 10.3389/fnagi.2014.00117Cortical spreading depression and mitochondrialdysfunction with aging: lessons from ethanol abuseGeorge E. Barreto1*, Francisco Capani2 and Ricardo Cabezas11 Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia2 Laboratorio de Citoarquitectura y Plasticidad Neuronal, Facultad de Medicina, Instituto de Investigaciones Cardiológicas Prof. Dr. Alberto C. Taquini (ININCA),UBA-CONICET, Buenos Aires, Argentina*Correspondence: gsampaio@javeriana.edu.coEdited by:Merce Pallas, University of Barcelona, SpainReviewed by:Enrico Sanna, University of Cagliari, ItalyRubem C. A. Guedes, Universidade Federal de Pernambuco, BrazilKeywords: cortical spreading depression, ethanol, mitochondria dysfunction, antioxidants, agingChronic consumption of ethanol has adamaging effect in various organs andmetabolic functions, including liver, kid-ney, heart, pancreas, and brain (Sun andSun, 2001; Bezerra Rde et al., 2005).Additionally, it has been shown that boththe acute and chronic ethanol intakeinduce alteration in voltage-gated chan-nels causing behavioral and electrophysio-logical changes in the brain (Little, 1999).In the last few years, the effect of ethanolin the electrophysiological phenomenon,known as cortical spreading depression(CSD), has been widely assessed (Sonnand Mayevsky, 2001; Bezerra Rde et al.,2005; Abadie-Guedes et al., 2008) as animportant model to predict the damagingeffects of ethanol in both young and agedbrains.Cortical spreading depression is a neu-ronal and glial depolarization wave in graymatter, which is thought to be associatedas an upstream event in migraine withaura, spontaneous intracerebral hemor-rhage, ischemic injury and brain trauma(Zhou et al., 2010; Dreier, 2011). Thisphenomenon has a duration of approxi-mately 1min and very slow propagation(2–5mm/min) when compared to actionpotentials, resulting in a suppression ofelectrical activity and disruption of ionhomeostasis (Bennett et al., 2008; Seideland Shuttleworth, 2011). This depolar-ization occurs when the extracellular K+concentrations increase above a thresh-old of 40mM, causing the CSD wavepropagation into adjacent cells. CSD alsorequires the activation of the N-methyl-D-aspartate (NMDA) subtype of glutamatereceptor, which facilitates the spread of thedepolarization wave (Eikermann-Haerterand Ayata, 2010).There are experimental evidences tosuggest that various factors influencethe brain CSD propagation, includingpharmacological substances, age, ethanolabuse and the insufficient ingestion ofantioxidants (Abadie-Guedes et al., 2008).To support this idea, previous reporthas shown that acute ethanol ingestionimpairs the CSD propagation when com-pared to chronic administration of 7, ormore days, in which this phenomenon issomehow stimulated (Bezerra Rde et al.,2005). Furthermore, it was previouslyreported that ethanol-treated rats hadalterations in the NADH oxidation cycleand a decrease in energy production andCSD wave frequency (Sonn andMayevsky,2001). Acute ethanol administration hasbeen also associated with the inhibition ofthe Na+-K+-ATPase pump function, theformation of free oxygen radicals and CSDregulation (Sonn and Mayevsky, 2001). Inthis aspect, ethanol increases lipid per-oxidation in the brain and the serumNO (nitric oxide) levels, probably dueto the activation of the inducible nitricoxide synthase (iNOS) by cytokines (Zimaet al., 2001). Chronic ethanol adminis-tration affects the antioxidant defenses ofthe brain by reducing the levels of glu-tathione, peroxidase, α -tocopherol, glu-tathione reductase and catalase (BezerraRde et al., 2005), and the aged brain is par-ticularly affected by this reduced antiox-idant scavenging system (Reiter, 1995).Indeed, it is possible that cytoplasmiccalcium levels may also be implicated inCSD deflagration (Torrente et al., 2014b).Altogether, these findings suggest thatthere are multiple mechanisms by whichethanol may damage the brain (Figure 1).Although one of the main mechanismsof ethanol-induced brain damage is dueto an augmented production of reactiveoxygen species (ROS), thus leading toincreased CSD propagation, this statementhas not been experimentally addressed.Most studies on CSD focused on the elec-trophysiological effects of ethanol abuse,and their reversion by some protectivemolecules, such as astaxanthin (Abadie-Guedes et al., 2008, 2012). To address thisconcern, it is important to point that (i)ethanol facilitates P450 2E1 activity, whichmetabolizes this compound and gener-ates ROS in the process; and (ii) ethanolincreases the levels of free iron in thecell, which also can promote ROS genera-tion. It is possible that most antioxidantsmay reverse, scavenge, or even impairthe production of free radicals and exertprotection through this pathway. Ethanolaffects the immune system in aged mice,suggesting that this might be one the mainmechanisms by which ethanol inducesneurodegeneration in aged brains (Drewand Kane, 2013; Kane et al., 2014).Interestingly, astrocytes have beenshown to be more resistant than neu-rons during ethanol-induced oxidativestress because of their greater contentof glutathione (GSH) and other antiox-idant enzymes (Watts et al., 2005; Barretoet al., 2011), and these cells may play animportant role in CSD (Torrente et al.,Frontiers in Aging Neuroscience www.frontiersin.org June 2014 | Volume 6 | Article 117 | 1AGING NEUROSCIENCEBarreto et al. CSD and ethanol with agingFIGURE 1 | Ethanol effects on CSD related processes. Ethanoladministration induces the inhibition of Na+-K+ -ATPase pump, depleting theATP contents of the cell, and causing the generation of ROS and lipidperoxidation. Both chronic and acute administration of ethanol has impairingeffects in CSD velocities, which in turn may reflect important alterations onthe bioenergetic metabolism. Additionally, ethanol increases the expressionof iNOS and the formation of NO, decreases the levels of antioxidantenzymes, like glutathione reductase and catalase, and promotes theactivation of GABA receptor related responses. The administration ofastaxanthin counteracts the effects induced by ethanol in CSD velocities.2014a). On the other hand, the disrup-tion of astrocyte oxidative metabolism,which results in ATP levels decline, hasbeen shown to increase the rate of spread-ing depression in rat cortex (Largo et al.,1997; Seidel and Shuttleworth, 2011),suggesting that metabolic alterations ofastrocytes are an important regulatorof CSD events, especially during nor-mal aging process (Farkas et al., 2011;Paradies et al., 2013; Yin et al., 2014). ATPdepletion is likely to occur due to the oxi-dation of ethanol to acetaldehyde catalyzedby alcohol/dehydrogenase containing thecoenzyme NAD+. The acetaldehyde is fur-ther oxidized to acetic acid and finally CO2and water through the citric acid cycle. Anumber of metabolic effects from ethanolare directly linked to the production of anexcess of both NADH and acetaldehyde.In this context, more NADH will dislocatethe equilibrium of converting glucose topiruvate for energy production toward aoverproduction of lactate and malate frompiruvate. The increased accumulation ofacetaldehyde by reduced conversion of thisproduct into acetic acid—both processesimpair mitochondrial functions and ener-getic metabolism—results in decreasedATP production. It is important to pointthat brain metabolism in the aged brain issomehow impaired, therefore the damag-ing effects of CSD are augmented (Farkaset al., 2011; Batista-De-Oliveira et al.,2012).Following a cortical spreading depres-sion event, metabolic recovery is compro-mised, as glucose and glycogen levels aresignificantly decreased and lactate levelsare found increased (anaerobic shuttle),thus leading to intense depolarization andcell death (Selman et al., 2004). In thiscontext, we hypothesize that aging influ-ences brain electrophysiological function-ing due to reduced metabolic shuttle andantioxidant defense, and the impairmentof both energy metabolism and redoxhomeostasis are a hallmark of brain aging(Yin et al., 2014). These observations areparticularly seen in older people withalcoholism problems. A previous studyreported that brain tissue loss was foundincreased in older subjects with alcoholismcompared to younger subjects with alco-holism (Oscar-Berman et al., 1997), andthis may accelerate normal aging processor cause premature aging of the brain.Importantly, ethanol was shown to impairvasodilatation enzymes such as nNOS(neuronal nitric oxide synthase) and eNOSFrontiers in Aging Neuroscience www.frontiersin.org June 2014 | Volume 6 | Article 117 | 2Barreto et al. CSD and ethanol with aging(endothelial nitric oxide synthase) by theaugmentation of ROS, and this was asso-ciated with an increase in ischemic braindamage in elder individuals (Sun et al.,2006).To counteract this damaging effectof ethanol on aged brain, and follow-ing CSD, different antioxidant moleculesand enzymes, such as α-tocopherol, ascor-bic acid, peroxiredoxin, and astaxan-thin are shown to be neuroprotectiveagainst ethanol intake in animal models(Bezerra Rde et al., 2005; Lee et al., 2010;Zhu et al., 2012). The carotenoid astax-anthin (3,3′-dihydroxy-β,β-carotene-4,4′-dione) has important metabolic functions,including its conversion to vitamin A,enhancement of immune response, inhibi-tion of NO and lipopolysaccaride (LPS)-induced inflammation, scavenging actionon reactive oxygen species, and protectionof gastric mucosa against ethanol-inducedinjuries (Kim et al., 2005; Lee et al.,2010). Astaxanthin was also shown toprotect against induced cerebral ischemiain rats by the inhibition on iNOS andinduce the expression of Hsp32 andHsp70, demonstrating a decrease in oxida-tive stress without affecting cell viability.This information supports the idea of anoxidative mechanism by which astaxan-thin may be exerting a protective effecton ethanol induced damage. On this per-spective, new findings on the antioxidanteffects of astaxanthin and their relation-ship with CSD were previously reported(Abadie-Guedes et al., 2012). In this study,the antagonistic effects of acute ethanolconsumption on CSD propagation in twogroups of rats with different ages wereassessed. Their main results showed thatCSD outcome was counteracted by astax-anthin administration. Age of animals andtime of ethanol/astaxantin administrationare the key features, and age related effectsof ethanol in the brain should be fur-ther addressed in additional experimentsrelated with ROS production in bothbrain and blood of the treated animals,as well as the expression of antioxidantenzymes such as iNOs or SOD (superox-ide dismutase). In this point of view, somehypotheses must be raised: (i) Perhaps, theantioxidant properties of astaxanthin onthe scavenging of ROS could explain thereversion of ethanol effect on CSD veloci-ties; and (ii) alternatively, it is possible thatethanol action on CSD involves an inter-action with the GABA-chloride ion chan-nels and the NMDA receptors, causing asuppression of nerve cell activity, throughionic modulation (Sonn and Mayevsky,2001; Criswell et al., 2003). Whether ornot this relationship between astaxanthinand the GABA is clear, this is a concernthat deserves further attention. Moreover,it is important to address the possible neu-roprotective effects of other antioxidantson the modulation of CSD in the settingof a pathophysiological condition, as ismigraine with aura, stroke or brain injury,and also in the normal aging process.REFERENCESAbadie-Guedes, R., Guedes, R. C., and Bezerra, R.S. (2012). The impairing effect of acute ethanolon spreading depression is antagonized by astax-anthin in rats of 2 young-adult ages. Alcohol.Clin. Exp. Res. 36, 1563–1567. doi: 10.1111/j.1530-0277.2012.01766.xAbadie-Guedes, R., Santos, S. D., Cahu, T. B.,Guedes, R. C., and De Souza Bezerra, R.(2008). Dose-dependent effects of astaxanthinon cortical spreading depression in chroni-cally ethanol-treated adult rats. Alcohol. Clin.Exp. Res. 32, 1417–1421. doi: 10.1111/j.1530-0277.2008.00710.xBarreto, G. E., Gonzalez, J., Torres, Y., andMorales, L. (2011). Astrocytic-neuronalcrosstalk: implications for neuroprotectionfrom brain injury. Neurosci. Res. 71, 107–113. doi:10.1016/j.neures.2011.06.004Batista-De-Oliveira, M., Lopes, A. A., Mendes-Da-Silva, R. F., and Guedes, R. C. (2012).Aging-dependent brain electrophysiologicaleffects in rats after distinct lactation conditions,and treadmill exercise: a spreading depres-sion analysis. Exp. Gerontol. 47, 452–457. doi:10.1016/j.exger.2012.03.016Bennett, M. R., Farnell, L., and Gibson, W. G.(2008). A quantitative model of cortical spreadingdepression due to purinergic and gap-junctiontransmission in astrocyte networks. Biophys.J. 95, 5648–5660. doi: 10.1529/biophysj.108.137190Bezerra Rde, S., Abadie-Guedes, R., Melo, F. R., Paiva,A. M., Amancio-Dos-Santos, A., and Guedes, R. C.(2005). Shrimp carotenoids protect the developingrat cerebral cortex against the effects of ethanol oncortical spreading depression. Neurosci. Lett. 391,51–55. doi: 10.1016/j.neulet.2005.08.040Criswell, H. E., Ming, Z., Griffith, B. L., andBreese, G. R. (2003). Comparison of effect ofof ethanol on N-methyl-D-aspartate- and GABA-gated currents from acutely dissociated neurons:absence of regional differences in sensitivity toethanol. J. Pharmacol. Exp. Ther. 304, 192–199.doi: 10.1124/jpet.102.041590Dreier, J. P. (2011). The role of spreading depression,spreading depolarization and spreading ischemiain neurological disease. Nat. Med. 17, 439–447.doi: 10.1038/nm.2333nm.2333Drew, P. D., and Kane, C. J. (2013). “Neuroimmunemechanisms of glia and their interplay withalcohol exposure across the lifespan,” in Neural-Immune Interactions in Brain Function andAlcohol Related Disorders, ed C. Cui (NewYork, NY: Springer Science + Business Media),359–386.Eikermann-Haerter, K., and Ayata, C. (2010). Corticalspreading depression and migraine. Curr. Neurol.Neurosci. Rep. 10, 167–173. doi: 10.1007/s11910-010-0099-1Farkas, E., Obrenovitch, T. P., Institoris, A., andBari, F. (2011). Effects of early aging andcerebral hypoperfusion on spreading depressionin rats. Neurobiol. Aging 32, 1707–1715. doi:10.1016/j.neurobiolaging.2009.10.002Kane, C. J., Phelan, K. D., Douglas, J. C., Wagoner,G., Johnson, J. W., Xu, J., et al. (2014). Effectsof ethanol on immune response in the brain:region-specific changes in adolescent versus adultmice. Alcohol. Clin. Exp. Res. 38, 384–391. doi:10.1111/acer.12244Kim, J. H., Choi, S. K., Choi, S. Y., Kim, H. K.,and Chang, H. I. (2005). Suppressive effect ofastaxanthin isolated from the Xanthophyllomycesdendrorhous mutant on ethanol-induced gas-tric mucosal injury in rats. Biosci. Biotechnol.Biochem. 69, 1300–1305. doi: 10.1271/bbb.69.1300Largo, C., Ibarz, J. M., and Herreras, O. (1997). Effectsof the gliotoxin fluorocitrate on spreading depres-sion and glial membrane potential in rat brain insitu. J. Neurophysiol. 78, 295–307.Lee, D. H., Lee, Y. J., and Kwon, K. H. (2010).Neuroprotective effects of astaxanthin in oxygen-glucose deprivation in sh-sy5y cells and globalcerebral ischemia in rat. J. Clin. Biochem. Nutr. 47,121–129. doi: 10.3164/jcbn.10-29Little, H. J. (1999). The contribution of electrophysi-ology to knowledge of the acute and chronic effectsof ethanol. Pharmacol. Ther. 84, 333–353. doi:10.1016/S0163-7258(99)00040-6Oscar-Berman, M., Shagrin, B., Evert, D. L., andEpstein, C. (1997). Impairments of brain andbehavior: the neurological effects of alcohol.Alcohol Health Res. World 21, 65–75.Paradies, G., Paradies, V., Ruggiero, F. M., andPetrosillo, G. (2013). Changes in the mitochon-drial permeability transition pore in aging and age-associated diseases. Mech. Ageing Dev. 134, 1–9.doi: 10.1016/j.mad.2012.12.006Reiter, R. J. (1995). Oxidative processes and antioxida-tive defense mechanisms in the aging brain. FASEBJ. 9, 526–533.Seidel, J. L., and Shuttleworth, C. W. (2011).Contribution of astrocyte glycogen stores to pro-gression of spreading depression and related eventsin hippocampal slices. Neuroscience 192, 295–303.doi: 10.1016/j.neuroscience.2011.05.006Selman, W. R., Lust, W. D., Pundik, S., Zhou, Y., andRatcheson, R. A. (2004). Compromised metabolicrecovery following spontaneous spreading depres-sion in the penumbra. Brain Res. 999, 167–174.doi: 10.1016/j.brainres.2003.11.016Sonn, J., and Mayevsky, A. (2001). The effect ofethanol on metabolic, hemodynamic and elec-trical responses to cortical spreading depression.Brain Res. 908, 174–186. doi: 10.1016/S0006-8993(01)02643-9Frontiers in Aging Neuroscience www.frontiersin.org June 2014 | Volume 6 | Article 117 | 3Barreto et al. CSD and ethanol with agingSun, A. Y., and Sun, G. Y. (2001). Ethanol and oxida-tive mechanisms in the brain. J. Biomed. Sci. 8,37–43. doi: 10.1159/000054011Sun, H., Molacek, E., Zheng, H., Fang, Q., Patel, K.P., and Mayhan, W. G. (2006). Alcohol-inducedimpairment of neuronal nitric oxide synthase(nNOS)-dependent dilation of cerebral arterioles:role of NAD(P)H oxidase. J. Mol. Cell. Cardiol. 40,321–328. doi: 10.1016/j.yjmcc.2005.11.004Torrente, D., Cabezas, R., Avila, M. F., Garcia-Segura,L. M., Barreto, G. E., and Guedes, R. C. (2014a).Cortical spreading depression in traumatic braininjuries: is there a role for astrocytes? Neurosci.Lett. 565C, 2–6. doi: 10.1016/j.neulet.2013.12.058Torrente, D., Mendes-Da-Silva, R. F., Lopes, A. A.,Gonzalez, J., Barreto, G. E., and Guedes, R. C.(2014b). Increased calcium influx triggers andaccelerates cortical spreading depression in vivo inmale adult rats. Neurosci. Lett. 558, 87–90. doi:10.1016/j.neulet.2013.11.004Watts, L. T., Rathinam, M. L., Schenker, S., andHenderson, G. I. (2005). Astrocytes protect neu-rons from ethanol-induced oxidative stress andapoptotic death. J. Neurosci. Res. 80, 655–666. doi:10.1002/jnr.20502Yin, F., Boveris, A., and Cadenas, E. (2014).Mitochondrial energy metabolism and redoxsignaling in brain aging and neurodegenera-tion. Antioxid. Redox Signal. 20, 353–371. doi:10.1089/ars.2012.4774Zhou, N., Gordon, G. R., Feighan, D., and Macvicar,B. A. (2010). Transient swelling, acidification, andmitochondrial depolarization occurs in neuronsbut not astrocytes during spreading depression.Cereb. Cortex 20, 2614–2624. doi: 10.1093/cer-cor/bhq018bhq018Zhu, H., Santo, A., and Li, Y. (2012). The antiox-idant enzyme peroxiredoxin and its protectiverole in neurological disorders. Exp. Biol. Med.(Maywood) 237, 143–149. doi: 10.1258/ebm.2011.011152Zima, T., Fialova, L., Mestek, O., Janebova, M.,Crkovska, J., Malbohan, I., et al. (2001). Oxidativestress, metabolism of ethanol and alcohol-related diseases. J. Biomed. Sci. 8, 59–70. doi:10.1159/000054014Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 15 April 2014; accepted: 25 May 2014;published online: 10 June 2014.Citation: Barreto GE, Capani F and Cabezas R (2014)Cortical spreading depression and mitochondrial dys-function with aging: lessons from ethanol abuse. Front.Aging Neurosci. 6:117. doi: 10.3389/fnagi.2014.00117This article was submitted to the journal Frontiers inAging Neuroscience.Copyright © 2014 Barreto, Capani and Cabezas.This is an open-access article distributed under theterms of the Creative Commons Attribution License(CC BY). The use, distribution or reproduction in otherforums is permitted, provided the original author(s) orlicensor are credited and that the original publicationin this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduc-tion is permitted which does not comply with theseterms.Frontiers in Aging Neuroscience www.frontiersin.org June 2014 | Volume 6 | Article 117 | 4

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Cortical Spreading Depression and mitochondrial dysfunction with aging: Lessons from ethanol abuse

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Cortical spreading depression and mitochondrial dysfunction with aging: lessons from ethanol abuse

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