neurotoxicity and mechanisms of induced hyperexcitability

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EDITORIAL EDITORIJAL EDITORIAL EDITORIJAL EDITORIAL EDITORIJALHOMOCYSTEINE: NEUROTOXICITY AND MECHANISMSOF INDUCED HYPEREXCITABILITYStanojlovic Olivera, Hrncic Dragan, Rasic-Markovic Aleksandra and Djuric DraganInstitute of Medical Physiology “Richard Burian”, School of Medicine, University of Belgrade, Belgrade, SerbiaHOMOCISTEIN: NEUROTOKSIČNOST I MEHANIZMIINDUKOVANE HIPEREKSCITABILNOSTIStanojlović Olivera, Hrnčić Dragan, Rašić-Marković Aleksandra i Đurić DraganInstitut za Medicinsku fiziologiju ”Rihard Burijan”, Medicinski fakultet, Univerzitet u Beogradu, Beograd, SrbijaReceived / Primljen: 09. 02. 2011.ABSTRACTWithin the past four decades, investigators worldwidehave established that the amino acid homocysteine (Hcy) isa potent, independent, novel and emerging risk factor for arteriosclerosis.In addition, Hcy is considered a vasotoxic andneurotoxic agent that interferes with fundamental biologicalprocesses common to all living cells. The aim of this article isto present data addressing central nervous system hyperexcitabilityin experimental models of homocysteine-inducedseizures. These results demonstrate that acute administrationof homocysteine and homocysteine-related compoundssignificantly affects neuronal activity, electroencephalographic(EEG) recordings and behavioural responses in adultWistar male rats. It is suggested that hyperhomocysteinemiamay generate similar effects on human brain activity. Homocysteineand D,L-homocysteine thiolactone are excitotoxicand elicit seizures through stimulation of NMDA receptors.In addition, they inhibit Na + /K + -ATPase activity in the cortex,hippocampus and brain stem. Nitric oxide (NO) acts asan anticonvulsant in D,L-homocysteine thiolactone-inducedseizures and prevents D,L-homocysteine thiolactone-inducedinhibition of Na + /K + -ATPase activity. EEG monitoring for theeffects of ethanol on homocysteine-induced epilepsy supportthe idea that ethanol intake could represent one of the exogenousfactors influencing brain excitability. Finally, it wasfound that homocysteine thiolactone significantly inhibitsacetylcholinesterase (AChE) activity in rat brain tissue.Keywords: homocysteine, CNS, hyperexcitability, ratAbbreviations used:AchE - acetylcholinesteraseBHMT - betaine-Hcy S-methyltransferaseCNS - central nervous systemEEG - electroencephalographyHcy - homocysteineNO - nitric oxideSWDs - spike-wave dischargestHcy - total plasma homocysteineSAŽETAKČetiri decenije istraživačkog rada širom sveta dovele su doustanovljavanja semi-esencijalne sulfihidrilne aminokiselinehomocisteina (Hcy) kao novog potentnog i nezavisnog faktorarizika za arteriosklerozu, kao i vazotoksične i neurotoksičnesupstance koja učestvuje u fundamentalnim biološkim procesimasvojstvenim svim živim ćelijama. Cilj ovog rada je daprikaže dostupna saznanja na temu hiperekscitabilnosti centralnognervnog sistema u eksperimentalnom modelu homocisteinomindukovene epilepsije. Rezultati pokazuju da akutnaadministracija homocisteina i homocisteinu-srodnih supstanciznačajno utiče na nervnu aktivnost, elektroencefalografske(ЕЕG) zapise i ponašanje odraslih mužjaka soja Wistar pacova,a smatra se da hiperhomocisteinemija može imati slične efektei na aktivnost ljudskog mozga. Homocistein i D,L-homocisteintiolakton su ekscitotoksični i izazivaju epileptične napade stimulacijomNMDA receptora; oni indukuju značajnu inhibiciju aktivnostiNa + /K + -ATPaze u korteksu, hipokampusu i moždanоmstablu. Azot monoksid (NO) deluje kao antikonvulzant u D,Lhomocisteintiolakton indukovanim epileptičnim napadima ivrši prevenciju D,L-homocistein tiolakton indukovane inhibicijeaktivnosti Na + /K + -ATPaze. EEG monitoring efekata etanola nahomocisteinom indukovanu epilepsiju podržava ideju da akutniunos etanola može predstavljati jedan od faktora egzogenoguticaja na moždanu ekscitabilnost. Takođe je utvrđeno da D, L-homocistein tiolakton u značajnom procentu inhibira aktivnostacetilholinesteraze u mozgu pacova.Ključne reči: homocistein, CNS, hiperekscitabilnost, pacovKorišćene skraćenice:AchE – acetilholin esterazaBHMT - betain-homocistein S-metiltransferazaCNS – centralni nervni sistemEEG - elektroencefalografijaHcy - homocisteinNO – azot monoksidSWDs – “šiljak pražnjenja”tHcy – ukupni plazma homocisteinUDK 612.8:577.112.34 ; 616.853 / Ser J Exp Clin Res 2011; 12 (1): 3-9Correspondence to: Dragan M. Djurić, M.D. Ph.D. Institute of Medical Physiology “Richard Burian”, School of Medicine, University of Belgrade,Višegradska 26/II, 11000 Belgrade, Serbia, Tel: +381-11-3607-112, Fax: +381-11-36 11 261, e-mail: drdjuric@eunet.rs3
BACKGROUNDWithin the past four decades, investigators worldwidehave established that the amino acid homocysteine (Hcy)is a novel and independent risk factor for arteriosclerosis.In addition, Hcy is a vasotoxic and neurotoxic agent thatinterferes with the fundamental biological processes commonto all living cells. Therefore, it has also been termedthe “cholesterol of the 21 st century.”Metabolism of homocysteine is coordinately regulatedto maintain a balance between remethylation and transsulfurationpathways, which are critical to maintaininglow levels of this potentially cytotoxic sulphur containingamino acid (1). Homocysteine belongs to a group of moleculesknown as cellular thiols and is considered a “bad”thiol. Glutathione and cysteine, the most abundant cellularthiols, are considered to be “good” thiols (2). In the methylationpathway that occurs in all tissues, homocysteineacquires a methyl group to form methionine in a vitaminB12 dependent reaction, which is catalysed by methioninesynthase. The second substrate required by methioninesynthase is 5-methyltetrahydrofolate, which is formed bythe reduction of 5,10-methylenetetrahydrofolate. This reactionis catalysed by the enzyme methylenetetrahydrofolatereductase (MTHFR). The TT genotype of this enzymecauses thermolability and reduces enzyme activity, whichimpairs the formation of 5-methyltetrahydrofolate. Thisreduced enzyme activity explains why this genotype is associatedwith increased Hcy levels when the folate status isrelatively low. However, liver, kidney and the lens of the eyehave the ability to convert Hcy to L-methionine througha vitamin B12-independent reaction catalysed by betaine-Hcy S-methyltransferase (BHMT). The CNS lacks BHMTand it is completely dependent on the folate and vitaminB12 pathway for the conversion of Hcy to L-methionine.Homocysteine condenses with serine to form cystathioninein an irreversible reaction catalysed by the B6containing enzyme cystathionine beta-synthase, which isknown as the transsulfuration pathway. Hcy catabolism requiresvitamin B6 and as a consequence, alterations in folicacid and B vitamin status impairs Hcy biotransformation.These alterations result in the synthesis of cysteine, taurineand inorganic sulphates that are excreted in urine.Elevation of homocysteine levels is known to lead to themetabolic conversion and inadvertent elevation of homocysteinethiolactone, which is a reactive thioester representingless than 1% of total plasma homocysteine. In all cell types,from bacteria to human, homocysteine is metabolised to homocysteinethiolactone by methionyl-tRNA synthetase (3).Homocysteine thiolactone causes lethality, growth retardation,blisters and abnormalities in somite development by oxidativestress, which is one of important mechanisms for its toxicity toneuronal cells (4). The highly reactive and toxic homocysteinemetabolite, homocysteine thiolactone, can be produced in twosteps by enzymatic and/or non-enzymatic reactions in bloodserum. The ability to detoxify or eliminate homocysteine thiolactoneis essential for biological integrity (3, 4).Total plasma Hcy (tHcy) consists of a pool of free homocysteine,homocystine, Hcy-S-S-Cys disulphide, proteinbound N- and S-linked Hcy as well as their oxidisedforms and Hcy-thiolactone (5-7). Under physiologicalconditions, less than 1% of the total Hcy is present in afree reduced form. Approximately 10–20% of total Hcy ispresent in different oxidised forms, such as Hcy-Cys andhomocystine, which is a Hcy dimer. Plasma tHcy levels areaffected by genetic, physiologic (age and sex) and lifestylefactors as well as various pathologic conditions (5, 6, 8).Hyperhomocysteinemia is defined as an elevated plasmatotal homocysteine (tHcy) concentration (>15 μM).Elevated tHcy is a recognised risk factor for cardiovasculardisease (9) and has been linked to neurological diseasesduring aging, such as cognitive declines, cerebrovasculardisease and stroke, vascular dementia and Alzheimer’sdisease. In addition, elevated tHcy levels are linked withpathological brain functioning, such as mental retardation,depression, schizophrenia and memory impairment.Hcy is also a pro-thrombotic and pro-inflammatory factor,vasodilatation impairing substance and an endoplasmaticreticulum stress inducer (10, 11).Mitrovic et al. (12) evaluated total plasma homocysteinein patients with angiographically confirmed coronary arterydisease. In addition, they investigated the effects ofhomocysteine lowering therapy on endothelial function,carotid wall thickness and myocardial perfusion. Theirstudy found that homocysteine levels decreased significantly(34%) with folic acid therapy and that endotheliumfunction improved by 27% with this treatment. However,carotid structure and myocardial perfusion did not showany significant improvement in patients with confirmedcoronary artery disease (13). Djuric et al. (14, 15) also investigatedthe link between homocysteine and folic acid,demonstrated folic acid induced coronary vasodilationand decreased oxidative stress in the isolated rat heart.HOMOCYSTEINE AND NEUROTOXICITYDespite several theories, a complete understanding ofHcy toxicity remains unclear. In particular, the hypothesisthat relates homocysteine to CNS dysfunction by way ofovert neurotoxicity is based on the neuroactive properties ofhomocysteine. Elucidating the link between homocysteineand CNS dysfunction is vital for improving the treatmentof homocysteine related CNS disorders. Hcy adversely affectsbrain functioning (i.e., mental retardation, dementiaand memory impairment) and high tissue concentrationscause oxidative stress and excitotoxicity in neurons (16).When these symptoms are combined with homocystinuria,patients often present with convulsions (17). These studiesprovide evidence for a complex and multifaced relationshipbetween homocysteinemia and CNS disorders. Hcy isan endogenous compound that is neurotoxic at supraphysiologicalconcentrations and induces neuronal damage andcell loss through excitotoxicity and apoptosis. These CNS4
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