neurotoxicity and mechanisms of induced hyperexcitability

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pathologies could be a direct consequence of the inabilityof cerebral tissue to metabolise Hcy through the betaineand transsulfuration pathways, thereby favouring Hcy accumulationin the nervous system (18). High brain concentrationsof either Hcy or its oxidised derivatives have beenshown to alter neurotransmission (19). The accumulationof homocysteine (at synapses or in the extracellular space)increases intracellular S-adenosylhomocysteine (SAH),which is a potent inhibitor of many methylation reactionsthat are vital for neurological function including the O-methylation of biogenic amines. Methylation of myelinbasic protein and reducing the synthesis of phosphatidylcholine, which can lead to blood-brain barrier (BBB) disruption,are a few pathological processes that are possiblein the absence of normal methylation patterns (20).It has been recently suggested that Hcy toxicity is aconsequence of its covalent binding to proteins, which interfereswith protein biosynthesis and decreases the normalphysiological activity of proteins. This modificationof protein function is a process called homocysteinylation.Transthyretin is a plasma protein that is modified throughhomocysteinylation (3, 21). Other reports suggest that Hcyexerts its toxicity through the induction of endoplasmic reticulum(ER) stress. Increased intracellular Hcy concentrationsare associated with both the alteration of redox balanceand post-translational protein modifications throughN- and S-homocysteinylation (22). Other studies suggestthat Hcy induces the expression of superoxide dismutasein endothelial cells, which leads to the consumption of NOand impairs endothelial vasorelaxation (23).HOMOCYSTEINE AND SEIZURESExperimental models of generalised clonic-tonic seizuresinduced by metaphit (1-[1(3-isothiocyanatophenyl)-cyclohexyl] piperidine) (24, 25) and lindane (γ-1,2,3,4,5,6-hexachlorocyclohexane) (26, 27) are widely used for thestudy of epilepsy and the preclinical evaluation of potentialantiepileptic treatments. In contrast to audiogenic epilepsyinduced by metaphit with its typical and characteristicthree degrees of intensity, the lindane model is similar toHcy-induced epilepsy with a wide spectra of behaviouralmanifestations (e.g., hot plate reaction and Kangaroo position)incorporated into the rating scale from grades 0 - 4.Almost four decades ago, Sprince et al. (28) described thatelevated levels of homocysteine arising from excess dietarymethionine may induce epilepsy and lethality. The fact thatincreased homocysteine concentrations damage endothelialstructures and the blood coagulation system duringaging and in patients on antiepileptic drugs (29) justifiesthe attention directed toward the examination of homocysteine’sneural effects.Furthermore, experimental models of epilepsy may beinduced by manipulations of γ-aminobuturic acid (e.g., bicuculline,corasol, picrotoxin and benzylpenicillin sodium)(30). In contrast, epilepsy can be induced by an oppositemechanism such as by increasing cerebral excitatory neurotransmission.There are several proposed mechanismsby which exposure to excess D,L-homocysteine or D,L-homocysteinethiolactone induce seizures. The most reactivenatural amino acid is homocysteic monocarboxylic, whichis sulphur-containing and its homocysteic sulphinic acidderivatives are excitatory amino acids that have been proposedas candidates for brain excitatory neurotransmitters(31). However, answering the question as to whether D,Lhomocysteinethiolactone should be included in the list ofepileptogenic factors according to behavioural and electrographicresponses will require additional studies andfuture human therapeutic trials. Increased levels of Hcyand its oxidised forms can provoke seizures by increasingactivation of certain neuronal receptors such as N-methyld-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate ionotropic glutamatereceptors or group I and group III metabotropic glutamatereceptors (5). All of these glutamate receptors areexpressed in hippocampal pyramidal cells and may directlyinduce or drive these cells over the threshold for excitotoxiccell death. Overstimulation of these receptors triggerscytoplasmic calcium pulses, Ca2 + influx and intraneuronalcalcium mobilisation in the presence of glycine (32).Increased cytosolic Ca2 + concentrations affect enzymeactivities and the synthesis of nitric oxide, which is a retrogrademessenger that overstimulates excitatory amino acidreceptors including glutamate, thereby lowering the convulsivethreshold (33). However, expression of the NMDAreceptor is not confined to neurons. Other cell types, includingendothelial cells from cerebral tissue, can expressthis receptor. Free radicals induce the up-regulation of theNR1 subunit of the NMDA receptor, thereby increasingthe susceptibility of cerebral endothelial cells to excitatoryamino acids, which can lead to blood brain barrier disruption(34). Microglia are also subject to the toxic effectsof Hcy (35). Hcy can induce convulsions in adults and inimmature experimental animals through modulating theactivity of metabotropic glutamate receptors (mGluRs)(36). Kubova et al. (37) stated that the main epileptic phenomenonin homocysteine thiolactone treated rats wasemprosthotonic, flexion seizures, which are observed inyoung animals but never seen in rats older than 25 days.Homocysteine was shown to elicit minor (predominantlyclonic) and major (generalised tonic-clonic) seizures duringontogenesis in immature Wistar rats (36, 37). It seemsthat Hcy exerts a direct excitatory effect comparable to theaction of glutamate (17). In addition, Hcy has been shownto enhance either the release or uptake of other endogenousexcitatory amino acids (36).Classical anticonvulsants such as phenytoin, carbamazepineand valproic acid lower plasma folate levels and significantlyincrease homocysteine levels, which induces epileptogenesisand reduces the control of seizures in patients withepilepsy (38). On the other hand, increasing excitability withthis native amino acid further contributes to epileptogenesisand disturbs the balance between excitation and inhibition in5
the brain. Following the work of Djuric’s study, Stanojlovic etal. administered homocysteine (i.p.) to adult rats, and for thefirst time, convulsive and non-convulsive seizures were recorded(39). This form of epilepsy was followed by two-wavepatterns of seizures with one replacing the other. It has beensuggested that D,L-homocysteine thiolactone may be consideredas an excitatory metabolite, which is capable of becominga natural convulsant if accumulated to a great extent inthe brain (39). Hyperhomocysteinemia in awake adult maleWistar rats induced a generalised seizure disorder characterisedby recurrent unprovoked clonic-tonic convulsions andabsence-like seizures as well as epileptic electrical discharges.In addition to a prolonged median latency to the first seizure,the seizure incidence, median seizure episode severity andmedian number of seizure episodes per rat were significantlyhigher in all Hcy treated groups (39). Non-convulsive statusepilepticus can occur from a variety of causes, includingprimarily generalised absence epilepsy, genetic origins (Wakayamaor tremor epileptic rats) or pharmacologically (penicillin,pentylenetetrazole or γ-hydroxy-butyric acid) inducedmodels (40). Behavioural immobility during motor cortexactivation and the occurrence of generalised spike-wave activityare among the most puzzling phenomena in absenceepilepsy. According to one of numerous hypotheses addressingthe development of spike-wave discharges (SWDs), theseelectrographic discharges may belong to the same class ofphenomena such as sleep spindles. Sleep spindals are normallygenerated sleep rhythms that transformation one, twoor more spindle waves into the spike component of the SWD(41). Cortico-thalamo-cortical oscillatory network connectionsmay play a pacemaker role in the electrogenesis of oscillationsand primarily represent the neurophysiological basisunderling the initiation and propagation of SWD (40).In keeping with the well-known fact that rhythmicbursts of spikes represent an electrophysiological markerof a hyperexcitability, Folbergrova et al. (42) found a verypoor electroclinical correlation between electroencephalographic(EEG) patterns and motor phenomena in immaturerats. The epileptogenic process is closely associated with thechanges in neuronal synchronisation, and non-convulsive,generalised epilepsy is characterised by brief episodes of unpredictableand unresponsive behaviours with a sudden arrestaccompanied by SWDs. However, the spike-wave complexesof SWDs have a unique shape. Bilateral, high-voltage,synchronous, spindle-like electrical oscillations, which arecommon phenomenon during paroxysmal EEG attacks,are termed SWDs. These are associated with sudden motorimmobility and minor clinical signs, such as the loss ofresponsiveness with rhythmic twitches of vibrissae or cervicofacialmusculature and are seen after i.p. administrationof D,L-homocysteine thiolactone in adult rats. Interestingly,absence-like animals showed no reaction to these differentstimuli (e.g., audiogenic, tactile).Stanojlović et al. (39) found poor electro-clinical correlationsin Hcy treated rats. It is worth mentioning that electrographicseizure discharges were absent even during motorconvulsions of grade 3 or 4. On the contrary, EEG seizureswithout motor symptoms were regularly observed. Theseaforementioned EEG signatures were distinguishable fromsleep spindles (10-16 Hz) in regard to their frequency, duration,morphology (sleep spindles are more stereotyped thanSWD waves) and moment of occurrence. For example, SWDsoccur during passive wakefulness, while sleep spindle-like oscillationsoccur during high amplitude delta activity (43). Thepoor prognosis for the Hcy group of animals appears to be aresult of the combined systemic damage caused by continuousseizure activity as well as the excitotoxic and neurotoxiceffects of homocysteine accompanied by the action of freeradicals, including oxidative brain damage (42, 44). In most ofthe related studies, it is not quite clear whether the observedeffects are due to homocysteine itself or to homocysteine metabolites.Notably, all of the above mentioned mechanisms inducecell death (45) and result in a high mortality rate (100%).The basic function of the Na + /K + -ATPase is to maintainthe high Na + and K + gradients across the plasma membraneof animal cells and it is essential for the generation of themembrane potential and maintenance of neuronal excitability(2). In addition, it has been demonstrated that thereis a moderate inhibition of rat hippocampal Na + /K + -ATPaseactivity by D,L-homocysteine, which is not observed in thecortex and brain stem (46). In contrast, D,L-homocysteinethiolactone strongly inhibits Na + /K + -ATPase activity incortex, hippocampus and the brain stem of rats, therebyaffecting the membrane potential with deleterious effectsfor neurons. Considering that hyperhomocysteinemia increasesformation of superoxide and hydrogen peroxideand that excitotoxicity indirectly provokes increased intracellularfree radicals production, it is feasible that oxidativestress may also be associated with the CNS injury causedby homocysteine and D,L-homocysteine thiolactone (47).Otherwise, nitric oxide (NO) is a highly reactive secondmessenger molecule synthesised in a number of tissues.It serves a key role in interneuronal communicationsvia modulating release of classical neurotransmittersand influencing the excitability status of neurons (33). Itis produced from L-arginine by the action of a family ofenzymes known as NO synthases (NOS). Neural (nNOS)and endothelial NOS (eNOS) are Ca 2+ /calmodulin-dependentenzymes, while inducible NOS (iNOS) shows Ca 2+ -independent properties. N-nitro-L-arginine methyl ester(L-NAME) is a non-selective NOS inhibitor commonlyused to decrease NO levels. Recently, it has been determinedthat NO serves a role in the mechanisms underlyingD,L homocysteine thiolactone induced seizures. Thiswas demonstrated by testing the action of L- arginine (NOprecursor) and L-NAME (NOS inhibitor) on behaviouraland EEG manifestations of D,L homocysteine thiolactoneinduced seizures (48). Following Djuric’s study, Hrncic etal. (48) showed functional involvement of NO in the convulsiveactivity of D,L-homocysteine thiolactone inducedseizures in adult rats. Pretreatment with L-NAME in adose–dependent manner increased seizure incidence andseverity and shortened latency time to the first seizure followinginjection with a subthreshold dose of D,L-homo-6
Page 2 and 3: Editor-in-ChiefSlobodan JankovićCo
Page 4 and 5: EDITORIAL EDITORIJAL EDITORIAL EDIT
Page 8 and 9: cysteine thiolactone (5.5 mmol/kg,
Page 10: 30. Shandra AA, Godlevskii LS, Brus
Page 13 and 14: INTRODUCTIONSchizophrenia is a chro
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Page 17 and 18: with the other rats. After a saline
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Page 22 and 23: ORIGINAL ARTICLE ORIGINALNI NAUČNI
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Page 30 and 31: ORIGINAL ARTICLE ORIGINALNI NAUČNI
Page 32 and 33: B) Spontaneous modelsThe most frequ
Page 34 and 35: Mouse/rat model Phenotype Reference
Page 36: 40. Ehses JA, Lacraz G, Giroix MH,
Page 39 and 40: INTRODUCTIONCardiovascular diseases
Page 41 and 42: REFERENCES1. Parfrey PS. Cardiac di
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Page 47: CIP - Каталогизација

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