Transactions of the Royal Society of Tropical Medicine and Hygiene (2008) 102, 1025—1031

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Lipid peroxidation in the cerebrospinal fluidof patients with neurocysticercosis

Ulises Rodrígueza, Camilo Ríosa, Tere Coronaa, Beatriz Talayerob,Patricia Ostrosky-Wegmanc, Luis A. Herrerab,∗

a Instituto Nacional de Neurología y Neurocirugía (INNN), Secretaría de Salud (SSA), Mexico City, Mexicob Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas/Instituto Nacional de Cancerología(IIB-INCan), Mexico City, Mexicoc Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico

Received 14 March 2008; received in revised form 6 June 2008; accepted 6 June 2008Available online 16 July 2008

KEYWORDSNeurocysticercosis;Lipid peroxidation;Micronuclei;Chromosome-defective;DNA damage;Cancer;Peripheral blood

Summary The variety of symptoms observed in patients with neurocysticercosis (NCC) isassociated with the generation of reactive species by inflammatory cells. Reactive species candamage the cell membrane, inducing lipid peroxidation (LP) and giving rise to genotoxic freeradicals. In this study we investigated the presence of LP products in cerebrospinal fluid (CSF)and the frequency of DNA damage in peripheral lymphocytes from 25 patients with NCC. Patientswith NCC showed higher LP levels compared to controls (n = 7), especially patients presentingwith severe symptoms. There was a significant correlation between LP and the inflammatoryresponse (Spearman’s correlation coefficient 0.75, P < 0.01). The presence of free radicals in thecentral nervous system (CNS) may favour the development of severe clinical symptoms, even inpatients under anti-inflammatory treatment but with a poor response. DNA damage correlatedwith the presence of LP and with symptom severity (correlation coefficient 0.30, P < 0.05, and0.54, P < 0.01, respectively). These results demonstrate the generation of oxidative damage inthe CNS of patients with NCC, which may be responsible for the severity of the symptoms. LP

determination in the CSF of patients with NCC could be used to determine the inflammatoryreaction developed.© 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rightsreserved.

∗ Corresponding author. Instituto de Investigaciones Biomédicas,Departamento de Medicina Genómica y Toxicología Ambiental,UNAM, P.O. Box 70-228, Ciudad Universitaria, 04510 México, D.F.,México. Tel.: +52 55 5628 0425; fax: +52 55 5628 0432.

E-mail address: herreram@biomedicas.unam.mx (L.A. Herrera).

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0035-9203/$ — see front matter © 2008 Royal Society of Tropical Medicindoi:10.1016/j.trstmh.2008.06.004

. Introduction

eurocysticercosis (NCC) is the most frequent parasiticnfection of the central nervous system (CNS) (Pittella,997); it is endemic in several parts of the world, mainlyn Latin America, Africa and Asia (Sciutto et al., 2000). It islso frequent in developed countries with high immigration

e and Hygiene. Published by Elsevier Ltd. All rights reserved.

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ates (Sorvillo et al., 2007; White and Atmar, 2002). NCCccurs when cysticerci, the larval stage of Taenia solium,re located within the CNS producing a variety of clinicalanifestations that depend on the number and location of

ysts, as well as on the host immune response to the par-site, which may vary from complete tolerance to intenseeaction (Bueno et al., 2004; Chavarría et al., 2005; Fleury etl., 2004; Flisser et al., 1986; Sotelo and Del Brutto, 2000).

The host-parasite relationship established during NCC isather complex. A chronic inflammatory process is com-only present throughout the natural history of NCC. The

everity of this inflammation depends on the localizationf cysticerci; for instance, if they are located within theubarachnoid space a severe inflammatory response is devel-ped by the majority of patients (Sotelo and Del Brutto,002). An important feature of any chronic inflammatoryeaction is the production of reactive oxygen and nitro-en species that are able to damage tissues surroundinghe inflammatory site (Bartsch and Nair, 2005). Oxidativeamage to DNA, proteins and lipids can ultimately lead toutcomes such as disorganization, dysfunction and destruc-ion of membranes, enzymes and proteins (Halliwell andhirico, 1993). Specifically, peroxidation of membrane lipidsay cause impairment of membrane function, decreaseduidity, inactivation of membrane-bound receptors andnzymes, increased permeability to ions and eventually,embrane rupture (Hardy et al., 2005).Lipid peroxidation (LP) is known to occur during inflam-

ation (Nair et al., 2007; Poli et al., 2008; Vidali et al.,008). It can be induced by free radicals and reactive oxygenpecies produced by phagocytes in the respiratory burst ands likely to contribute to tissue damage (Nair et al., 2007).eroxyl radicals are the primary free radical intermediatef LP, a chain reaction which propagates through cellularembranes during conditions of oxidative stress (Poli et al.,

008). Decomposition of peroxyl radicals terminates freeadical propagation and results in the production of reactiveldehyde end-products. These compounds can react withNA bases and form mutagenic adducts (Nair et al., 2007).eroxyl radicals can induce extensive oxidative DNA baseamage causing mutations in human cells, as well as induceNA strand breaks by oxidative attack on the DNA backbone.

LP is thought to be an important factor in the patho-hysiology of a number of diseases and in ageing (Dmitriev,007; Halliwell and Gutteridge, 1990; Kopitz et al., 2004;endoza-Núnez et al., 2007). Elevation of LP products haseen reported in the cerebrospinal fluid (CSF) of patientsith pneumococcal meningitis (Aycicek et al., 2007; Kleint al., 2006). The aim of the present study was to evalu-te the presence of LP products in the CSF of patients withCC, and its potential association with the severity of the

nflammatory reaction and the clinical presentation of NCC.e also investigated the frequency of micronuclei (MN) ineripheral lymphocytes of these patients and correlated itith the presence of LP in CSF.

. Materials and methods

.1. Selection of cases and controls

he study included 25 patients: 13 male and 12 femaleho attended the Neurology Out-Patient Department of

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he National Neurology and Neurosurgery Institute of Mex-co (INNN) between 2000 and 2004. NCC was diagnosedy standard clinical, radiological and serological criteria.he median age was 40 years (range 20—60). Patients werelassified according to the severity of their clinical symp-oms. Group I consisted of six patients who presented witheadache and seizures that were easily managed with anti-onvulsive therapy. Group II included 19 patients, of whom4 presented with hydrocephalus and elevated intracranialressure. Additionally, Group II was further divided intoub-groups A (eight patients without previous steroidal anti-nflammatory therapy) and B (11 patients receiving steroidherapy).

Seven individuals, one male and six females, in whom aiagnosis of NCC was completely ruled out according to allriteria, were studied as controls. Median age was 28 years.ive of these patients were diagnosed with migraine and twoith cryptogenic epilepsy.

.2. CSF sampling, cytochemical analysis and LPetermination

SF samples were obtained for diagnosis and clinical follow-p by lumbar puncture under aseptic conditions and werelaced into sterile tubes. CSF was processed for cytochem-cal analysis, which included white blood cell (WBC) countnd total protein evaluation, among other standard param-ters. Both WBC count and protein levels in CSF were usedo categorize the inflammatory response in controls andatients with NCC. A normal CSF count was <5 WBC/�lnd <45 mg total proteins/dl; if CSF had 5—10 WBC/�lnd/or 45—60 mg/dl total proteins, the inflammatory pro-ess was considered moderate, while a severe inflammatoryesponse was determined if CSF contained >10 WBC/�lnd/or >60 mg/dl total proteins.

To evaluate LP we determined the presence of lipid fluo-escent products, which are a solid index of lipoperoxidationn the CNS (Boll et al., 2008; Naidoo and Knapp, 1992).riefly, 0.5 ml of each undiluted CSF sample were taken andransferred into a sterile glass tube protected from lightxposure, mixed with 4 ml of chloroform-methanol (2:1),ently shaken for 2 min, and centrifuged at 10 000 rpm for0 min. After aspirating the superior aqueous phase, thentermediate skin was delicately moved to allow transfer of.5 ml of the organic phase (bottom layer) into clean tubesnd 1 ml of H2O was added. After shaking for 1 min, theixture was placed in ice for 15 min, the upper phase wasumped out and 1 ml of the organic phase was transferrednto a quartz cuvette and 100 �l of methanol was added.luorescence was measured in a luminescence spectropho-ometer (Perkin-Elmer LS50B; USA) at 370 nm of excitationnd 430 nm of emission. The sensitivity of the spectropho-ometer was adjusted to 140 fluorescence units (FU) with a.1 mg/l quinine standard solution in 0.05 M sulphuric acidolution. The results were expressed in FU/ml.

.3. Micronuclei assay

eripheral blood (0.5 ml) was cultured in 6 ml RPMI-1640edium (Sigma Chemical Co., St. Louis, MO, USA) sup-lemented with non-essential amino acids and glutamine

Oxidative damage in patients with neurocysticercosis 1027

Table 1 Cytochemical lipid peroxidation analysis of cerebrospinal fluid and micronucleus frequency in peripheral blood lym-phocytes from controls and patients with neurocysticercosisa

Group Age (years) WBC in CSF(cells/�l)

Protein in CSF(mg/dl)

LP products inCSF (FU/ml)

Micronucleiin bloodb

Controls (n = 7) 28 (25—65) 0 (0—10) 27 (10—53) 1 (0—3) 1 (0—3)Patients (n = 25) 40* (25—66) 2* (0—200) 45 (0—562) 1.1 (0—16.4) 5* (1—14)

WBC: white blood cells; CSF: cerebrospinal fluid; LP: lipid peroxidation products; FU: fluorescence units.

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a Values are shown as median (range).b Micronucleated lymphocytes/1000 binucleated cells.* Two-sided P < 0.05; Mann-Whitney U test with respect to control

(1%; Gibco, Grand Island, NY, USA). Lymphocyte prolifera-tion was stimulated by phytohaemagglutinin (0.2%, Gibco).Cultures were incubated at 37 ◦C for 72 h and cytochalasin-B (6 �g/ml, Sigma) was administered during the last 24 hof culture to block cytokinesis. The cytokinesis-block assayallows identification of the products of a single mitosisbecause the two daughter nuclei are maintained in the samecytoplasm. Cells were fixed with methanol-acetic acid (3:1),carefully dropped onto cold glass slides, and stained withWright’s stain for MN evaluation. MN frequency was analyzedin 1000 binucleate cells per donor according to publishedcriteria (Norppa and Falck, 2003). MN are fragments of themain nucleus and are considered an appropriate method formeasuring DNA damage both in vivo and in vitro (Fenech,2000; Herrera et al., 2000).

2.4. Statistical analysis

A Mann-Whitney U test was used to compare NCC patientswith controls. Two-tailed P values of <0.05 were consid-ered significant. Spearman’s test was applied to investigatecorrelations between LP, WBC counts and MN frequency.

3. Results

Table 1 presents the results of the cytochemical analysis ofCSF and the analysis of micronucleated cells in peripheralblood. The median frequency of micronucleated cells per1000 binucleated cells in controls was 1 (range 0—3), whilein patients with NCC this was 5 micronucleated cells (range1—14; P = 0.002). Patients were significantly older than con-trols.

Patients with NCC were divided into three groups interms of the severity of their clinical symptoms. Group Ipatients presented with headache and seizures that wereeasily managed with anticonvulsive therapy. These patientshad median disease duration from diagnosis to the time ofthe present study of 12 months (range 0—180) (Table 2). Allpatients’ computed tomography scans in this group showedcalcified parenchymal cysticerci (inactive disease). CSFcytochemical analysis consistently demonstrated a minimaldegree of inflammation. The frequency of micronucleated

cells in this group was between 2 and 5 in 1000 binucle-ated cells (median 3) and the difference from controls wasstatistically significant (P < 0.05).

Group II included patients presenting with cerebellarsyndrome or with hydrocephalus and elevated intracranial

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ressure, without previous steroidal anti-inflammatory ther-py (Group IIA) or receiving steroid therapy (Group IIB).roup IIA patients had median disease onset time of 20onths (range 1—120) (Table 2). The majority of patients

n this group had mixed-type NCC, with subarachnoid vesic-lar forms of the parasite (active disease) and parenchymalalcified forms. Three patients presented hydrocephaly andlevated intracranial pressure. Micronucleated cell fre-uency in this group was a median of 4.5/1000 binucleatedells (range 1—8) and, as in Group I patients, was statisticallyifferent from controls (P < 0.05).

Group IIB patients had a median disease onset time of8 months (range 8—180) (Table 2). All patients in thisroup had mixed-type NCC; the predominant forms wereesicular and colloidal. Six patients had received treatmentith albendazole and eight required a ventriculo-peritoneal

hunt. All parameters measured, apart from disease dura-ion, were significantly different from controls (P < 0.05).

Individuals were also grouped according to the sever-ty of the inflammatory process indicated by the CSF cellount and total protein concentration. Patients with nor-al CSF values presented a median LP level of 0 (Table 3),hile individuals with CSF values indicating a moderate or

evere grade of inflammation had median LP levels of 0.9nd 4.4, respectively. LP levels in CSF of patients with NCCxhibiting a severe inflammatory reaction were statisticallyifferent from those of individuals with normal CSF cyto-hemistry (P < 0.001, Mann-Whitney U test). There were alsotatistical differences in age, WBC and protein in CSF and inicronucleated cell frequency between groups (Table 3).Spearman’s correlation was performed between LP, MN

requency and cell counts in CSF. Significant correla-ions were found between cellularity and LP (correlationoefficient = 0.75, P < 0.01); cellularity and MN frequencycorrelation coefficient = 0.54, P < 0.01); and LP and MNrequency (correlation coefficient = 0.39, P < 0.05). Ageas also correlated with MN induction, however, theorrelation was not statistically significant (correlation coef-cient = 0.308, P = 0.09)

. Discussion

bnormalities in CSF cytochemical composition have been

eported in as many as 80% of patients with active NCC.hese abnormalities correlate with disease activity and loca-ion of parasites within the CNS. Inflammatory changes inhe CSF are largely related to extraparenchymal cyst loca-ion. The most consistent finding is moderate mononuclear

1028 U. Rodríguez et al.

Table 2 General characteristics of patients according to their diagnosis and clinical symptomsa

Age (years) Gender Diseaseduration(months)b

WBC in CSF(cells/�l)

Protein in CSF(mg/dl)

Inflammationc LP products inCSF (FU/ml)

Micronucleatedcellsd

Controls27 F 1 0 17 Normal 1.3 165 M 3 0 53 Moderate 1.0 225 F 2 0 30 Normal 1.0 031 F 6 10 49 Moderate 1.4 323 F 12 0 27 Normal 0.0 130 F 1 0 12 Normal 3.0 228 F 5 0 10 Normal 0.0 1

Median28 3 0 27 1.0 1

Group I38 F 18 0 0 Normal 0.0 436 M 7 15 40 Severe 7.7 540 F 0 0 0 Normal 0.0 226 F 12 0 18 Normal 0.0 240 F 180 1 19 Normal 1.1 437 F 12 2 33 Normal 0.7 2

Median37.5 12 0.5 18.5 0.4 3*

Group IIA32 M 24 0 0 Normal 0.0 342 M 6 0 10 Normal 0.0 845 F 72 10 46 Moderate 0.0 636 M 1 0 0 Normal 0.0 145 M 36 200 66 Severe 7.9 627 F 1 0 0 Normal 0.0 651 M 120 17 562 Severe 4.2 357 F 16 0 45 Normal 1.1 1

Median43.5 20 0 27.5 0.0 4.5*

Group IIB52 M 24 6 102 Severe 1.7 141 M 60 0 0 Normal 0.3 231 M 120 24 26 Severe 4.5 645 F 168 113 122 Severe 4.5 1244 F 68 61 541 Severe 2.0 825 M 18 45 72 Severe 2.2 1060 M 8 0 46 Moderate 0.7 1266 M 180 1 165 Severe 3.4 1439 F 16 4 142 Severe 6.1 1047 M 96 20 212 Severe 2.5 336 F 70 21 122 Severe 16.4 6

Median44* 68 20* 122* 2.5* 8*

WBC: white blood cells; CSF: cerebrospinal fluid; LP: lipid peroxidation; FU: fluorescence units.a Control: individuals in whom a diagnosis of neurocysticercosis (NCC) was ruled out by all criteria; Group I: patients with NCC whopresented with headache and seizures and who were easily managed with anticonvulsive therapy; Group IIA: patients with NCC withoutprevious steroidal anti-inflammatory therapy; Group IIB: patients with NCC receiving steroid therapy.b Period between diagnosis and enrolment in the present study.c Normal: WBC <5/�l and proteins <45 mg/dl; moderate inflammation: WBC 5—10/�l and/or proteins 45—60 mg/dl; severe inflammation:WBC >10/�l and/or proteins >60 mg/dl.d Micronucleated lymphocytes/1000 binucleated cells (median values).* Two-sided P < 0.05; Mann-Whitney U test with respect to controls.

Oxidative damage in patients with neurocysticercosis 1029

Table 3 Lipid peroxidation in cerebrospinal fluid and micronucleated cell frequency in peripheral lymphocytes of controls andpatients with neurocysticercosis presenting different inflammatory responsesa

Inflammatory response

Normal (n = 16) Moderate (n = 4) Severe (n = 12)

Age (years) 34 52.5* 44.5*

WBC/mm3 in CSF 0 (0—2) 5 (0—10) 21 (6—200)*

Protein (mg/dl) in CSF 11 (0—45) 48 (46—53) 122 (26—562)*

LP products in CSF (FU/ml) 0 (0—1.3) 0.9 (0—1.4) 4.4 (2.0—16.4)*

Micronucleated cells in peripheral blood b 2 (0—8) 4.5 (2—12) 6 (1—14)*

WBC: white blood cells; CSF: cerebrospinal fluid; LP: lipid peroxidation; FU: fluorescence units.a Values are shown as median (range).

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b Number of micronucleated cells/1000 binucleated cells.* Two-sided P < 0.01; Mann-Whitney U test.

pleocytosis, usually not exceeding 200—300 cells/�l. Proteinlevels are also elevated to 50—200 mg/dl. CSF glucose levelsare normal or moderately low.

In the present study we investigated the presence ofLP products in the CSF of patients with NCC. LP is knownto occur during inflammation, being induced by free radi-cals and reactive oxygen species produced by mononuclearcells in the respiratory burst (Bartsch and Nair, 2005). Ourresults indicate that patients with NCC present a wide rangein the levels of LP products in their CSF. Because patientswith NCC presented with a variety of clinical symptoms theywere grouped according to clinical symptom severity. Sig-nificantly higher LP product levels were detected in theCSF of group IIB patients compared with control individu-als. This group of patients included individuals presentingpredominantly vesicular and colloidal cysticerci. Althoughall group IIB patients were under steroid therapy, CSF cyto-chemical analysis indicated severe inflammatory responsesin the majority of these patients. This observation wasfurther confirmed when LP product levels were analyzedaccording to the severity of the inflammatory response inpatients and controls. Patients with CSF data indicatinga severe inflammatory response also presented the high-est LP product levels, which were statistically differentcompared with those observed in patients with normal ormoderate inflammatory responses. These results indicatethat the cysticerci-induced inflammatory response in theCNS of infected individuals causes oxidative damage thatcan be analyzed by LP product detection in the CSF.

It is interesting to note that LP levels were also elevatedin one Group I patient who presented calcified cysticercionly, and a severe inflammatory reaction. In general, thesepatients do not generate intense inflammation. Althoughsome reports indicate that a local inflammatory reactioncan develop in these patients (García et al., 2003; Nashet al., 2004), the inflammation observed in the CSF of thispatient most likely resulted from a parasite located in thesubarachnoid space.

Some patients with severe symptoms were treated with

albendazole and steroidal anti-inflammatory therapy. It hasbeen reported that the cysticidal agents albendazole andpraziquantel may induce inflammation during the first monthof treatment because they initiate a process that leads tocyst degeneration, granuloma formation and/or calcifica-

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ion (Estanol et al., 1986, 1989). This inflammatory responsean be present in some patients even after dexamethasonedministration. Our results show that high LP product lev-ls were present in patients with NCC treated with steroidalnti-inflammatory therapy, and suggest that this parameterould be a reliable measurement of the patient’s responseo steroidal drugs.

NCC has been associated with the presence of DNA dam-ge in peripheral blood lymphocytes, and some studies haveuggested that this infection could be associated with aigher risk for haematological and neurological tumours (Delrutto et al., 1997; Herrera et al., 2000, 2001). We there-ore investigated the frequency of micronucleated cellsn peripheral blood from controls and patients with NCC.icronucleus analysis is considered an appropriate method

or measuring DNA damage both in vivo and in vitro, regard-ess of whether the damage originated from clastogenic orneugenic events. In the present study, patients with NCCad a frequency of micronucleated cells higher than in unin-ected individuals, confirming previous observations. Therequency of micronucleated cells increased with symptomeverity; patients with cerebellar syndrome or with hydro-ephalus and elevated intracranial pressure had the highesticronucleated cell frequency in peripheral blood, even

f they were under steroidal anti-inflammatory treatment.imilarly, when patients were grouped according to theirnflammatory response in the CNS, individuals with a severenflammatory response had the highest micronucleated cellrequency.

Although the possible influence of albendazole in thenduction of micronucleated cells in treated patients can-ot be totally discarded, previous in vitro studies haveemonstrated that only high doses of albendazole signifi-antly increase micronucleated cell frequency (Ramírez etl., 2001, 2007). Furthermore, in vivo, albendazole is rapidlyetabolized into albendazole sulfoxide and sulfone, and

either of these metabolites produces this type of DNA dam-ge.

In conclusion, cysticercosis could induce free radical for-

ation in the CNS of infected individuals, mainly in patientsith active forms. This type of oxidative damage induced by

he parasite may be measured by the level of LP productsn the CSF and correlated directly with mononuclear cellounts and protein levels in the patient’s CSF. Whether the

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ncrease in the level of LP products represents a risk factoror patients with NCC to develop haematological malignan-ies is a question that deserves further investigation.

uthors’ contributions: LAH, UR and TC designed the studyrotocol; UR and TC carried out the clinical assessment; BTarried out lipid peroxidation and micronucleated cell anal-sis; LAH, CR and POW analysed and interpreted the data;AH drafted the manuscript. All authors read and approvedhe final manuscript. LAH is guarantor of the paper.

cknowledgements: We thank Clementina Castro for herechnical assistance.

unding: This project was partially supported by the Direc-ión General de Asuntos del Personal Académico, UNAM,éxico PAPIIT IX205004.

onflicts of interest: None declared.

thical approval: The protocol for this study was revisednd accepted by the Ethics Committee of the National Neu-ology and Neurosurgery Institute of Mexico, Mexico D.F. on5 August 2000 and by the Ethics Committee of the Nationalancer Institute of Mexico, Mexico D.F. on 19 October 2001.

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