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Cyclic Guanosine Monophosphate (CGMP),Nitrite and Nitrate in The å¡ ORIGINAL ARTICLE å¡ Cyclic Guanosine Monophosphate (CGMP), Nitrite and Nitrate in the Cerebrospinal Fluid in Meningitis, Multiple Sclerosis and Guillain-Barre Syndrome Masayuki Ikeda, Ikuko Sato, Takashi Matsunaga**, Mafuyu Takahashi**, Tatsuhiko Yuasa* and Sei-itsu Murota Recent evidence suggests the involvement of nitric oxide (NO) in inflammation and demyeli- nation in the brain. To test this hypothesis, we measured NOmarkers in the cerebrospinal fluid from patients with bacterial meningitis (BM), aseptic meningitis (AM), multiple sclerosis (MS), and Guillain-Barre syndrome (GBS). Subjects with non-inflammatory neurologic diseases served as the controls. NOmarkers were cyclic guanosine monophosphate (CGMP)measured with an enzymeimmunoassay, and nitrite and nitrate measured with the Griess reaction. Except for BM, CGMPwas not increased in AM,MSor GBScompared with the controls. Nitrite and nitrate were unaltered in any of the groups studied. These results do not support the hypothesis that NOis increased in the brain in meningitis, MSor GBS. Otherwise CGMP,nitrite and nitrate in the cerebrospinal fluid do not reflect the increase in NOin the brain. (Internal Medicine 34: 734-737, 1995) Keywords: nitric oxide, bacterial meningitis, aseptic meningitis Introduction Nitricneurotransmitteroxide (NO)(1),playsas amultiplevasodilatorroles(2),in andthe asbrain:an immuneas a andmediatorinjurious(3). actionsIn the (5,immune6) butsystem,its roleNOinhasbrainboth diseasesprotectiveremains(4) litisunknown.(7),In the animalmRNAexpressionmodels of meningitisof inducible(3) NOandsynthaseencepha- patients(iNOS) is withincreased.meningococcalIn humans,meningitisVisser ethaveal greatly(8) reportedincreasedthat (CSF)concentrationswhile Milstienof NOetmetabolitesal (9) observedin theonlycerebrospinala mild increasefluidin NOpatientsis implicatedwith meningitis.also in multiple sclerosis (MS). NOmedi- tionates intoxicityvitro (6).towardNOisoligodendrocytes,localized in the resultingspinal cordinofdemyelina-mice with malexperimentalmodel of allergicMS. mRNAencephalomyelitisexpression of iNOS(EAE)is (increased10), the ani-not Guillain-Barreonly in EAE(7), syndromebut also in(GBS)the brainis anotherof patientsinflammatorywith MS(1neu-1). rologic disease which is different fromAlthoughmeningitisNO-inducibleand MS. cytokines are increased in the CSF( 1 2) andThe serumpresent(13)studyin GBS,was undertakenthere has beennoto determinestudy onNOif NOin isGBS. differenceincreased inin meningitis,NOproductionMSinandtheseGBSanddiseases.if thereWeismeasuredany cyclicnitrate guanosine(NO3~), commonmonophosphatemarkers (CGMP),of NO(14),nitritein CSF(NO2~)fromand patients(AM), MSwithandbacterialGBS. meningitis (BM), aseptic meningitis Patients and Methods groupThe consistedpatients wereof29 dividedpatients into(agefive54.0±3.8groups,years)(i) withThe controlone of theheadache,followingcervicalnon-inflammatoryspondylosis, neurologicmyotonic diseases:dystrophy, tensionamyo- kinson'strophic lateraldisease. sclerosis,(ii) BM: agespinocerebellar48.7+5.9 years;degenerationn=9. Thepatientsor Par- had severe febrile illness, meningeal signs and polymorphonu- clear pleocytosis (650-12,000/|il) in CSF. The pathogenic bacteria were Neisseria meningitidis (n=2), Streptococcus From the Department of Physiological Chemistry, Graduate School and *the Department of Neurology, School of Medicine, Tokyo Medical and Dental University, Tokyo and **the Department of Neurology, Asahi General Hospital, Chiba Received for publication September 20, 1994; Accepted for publication April 19, 1995 Reprint requests should be addressed to Dr. Masayuki Ikeda, the Department of Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 1 13 734 Internal Medicine Vol. 34, No. 8 (August 1995) NO in Meningitis, MS and GBS pneumoniae (n=2), Streptococcus viridans (n= 1 ), Staphylococ- tively). cus aureus (n=l), unknown (n=3). (iii) AM: age 35.3±2.0 years; n= 15. The patients had fever, headache and CSF pleocy- Discussion tosis (50-900/|il) with mononuclear predominance. The clini- cal course was benign, (iv) MS (Relapsing-remitting type) ( 15): In the present study, CGMP,NO2~and NO3~, were generally age 34.6+4.1 years; n=13. All had active disease which was unaltered in the groups studied. The only significant change defined as an acute exacerbation with the occurrence of new was the increase in CGMPin BM. neurologic symptoms lasting more than 24 hours, (v) GBS:age In the animal model of meningitis, Campbell et al (3) 34.0+4.8 years; n=7. All had rapidly progressive motor weak- reported that the expression ofiNOSmRNAis increased in the ness of lower and upper extremities, areflexia and mild sensory glia of the inflammatory lesions. Visser et al (8) reported that signs. CSF showed normal cell counts in all subjects. The NO2~and NO3~are increased in CSFin patients with meningo- concentration of protein was increased in five patients. Two coccal meningitis while Milstien et al (9) observed only a mild patients had normal CSF protein initially with a later rise in increase in CSFNO3~in patients with BMand AM.In the subsequent lumbar punctures. present study, NO2"and NO3~in BMand AMremained similar CSF samples, obtained by lumbar puncture, were frozen to those in the controls. Multiple factors, i.e. pathogens, treat- immediately and stored at -80°C. Total protein, glucose, white ment and the status of the patients, could explain these discrep- blood cell counts and the presence of bacteria were tested by ant results. For example, Visser et al (8) focused on meningo- routine laboratory methods. The CGMPconcentration was coccal meningitis and studied 94 patients whereas our BM assayed in duplicate with a commercial enzyme immunoassay group included only two patients with meningococcal meningi- kit (Amersham). The samples (50 jul), acetylated in an acetic tis. It may be that only particular bacteria increase NOproduc- anhydride-triethylamine mixture, was incubated with 1 00 jul of tion in the brain. rabbit anti-CGMP serum at 4°C for 2 hours. Then 100 (il of Milstien et al (9) question ifNO2~ andNO3~ in CSF originate CGMP-peroxidaseconjugate wasaddedandthe sampleswere in the brain in meningitis. They indicated that the serum nitrate incubated at 4°C for 1 hour. After aspiration of unbound concentration, much greater than that in CSF, may contribute to conjugate, 200 jlxI ofenzyme substrate was added. A blue color, the increase in CSF nitrate through the damaged blood-brain which can be read at 630 nm, developed after the incubation at barrier. Another problem with NO2~and NO3~as NOmarkers room temperature for 30 minutes. is that they derive not only from the metabolism of NObut NO2~and NO3~(the latter after reduction to NO2~) were also from other sources, such as food (16). measured by a microplate version of the Griess reaction (14). CGMPmaynotbe a specific marker of NOin vivo as it is in NO3~was reduced to NO2~in the presence of 0. 1 U/ml nitrate vitro (14). The increase in CGMPwithout an increase in NO2" reductase (Aspergillus species; Boehringer-Mannheim). Then and NO3~,as in BMin the present study, suggests that the 2% sulfanilamide (150 \i\) in 1M H3PO4 was mixed with 100 \\1 activation of guanylate cyclase is caused by another molecule of the sample. After 10 minutes, 150 |jl of 0.2% (17). The lack of correlation between CGMPand NO2~and naphthylenediamine in water was added. The absorbance at 546 NO3~in the present study is additional evidence for the activa- nmwas measuredafter incubation at roomtemperature for 10 tion of guanylate cyclase without NO. minutes. As in inflammatory diseases in other tissues, NOproduction Statistical analysis was performed by means of Kruskal- is considered to be increased in meningitis (3) but previous Wallis test for multiple comparisons. Twoindividual mean studies have not all supported this hypothesis. First, investiga- values were compared post hoc with Dunnett's Mest. Regres- tors are not necessarily successful in inducing high-output NO sion analysis was done by the method of least squares. synthesis from humancells cultured in vitro by treatment protocols with cytokines that are highly effective with rodent Results cells (18, 19). Secondly, some inflammatory cytokines de- crease constitutive NOS(20) but increase the other type, iNOS. Figure 1 shows that the markers of NOwere generally Moreover, other cytokines which are increased in the CSFfrom unaltered in the patient groups studied. The CGMPconcentra- patients with BMinhibit even iNOS (21). These reciprocal tion in CSF in the control group was 2.4+0.4 nM. With the effects of cytokines can obscure the increase in NO,if any. exception of BM(10.4±2.6 nM, *p<0.05), CGMPwas not Lin et al (10) showed that NOis localized in the spinal cord increased in AM(2.5+1.1 nM), MS (2.3±0.6 nM) or GBS of mice with EAE. iNOS mRNAis increased both in the mouse (1.8±0.6 nM). NO2"andNO3-were unaltered inBM (0.56±0.08, brain with EAE (7) and in the brain of patients with MS(1 1). 7.4±0.6 nM respectively), AM (0.58±0.06, 8.7+1.6 jliM), MS Although these studies suggest that NOis increased in the MS (0.6210.07, 8.3+0.6 \jM) and GBS (0.58+0.06, 7.4+0.9 jiM) brain, NOmarkers in CSF were not increased in the present compared to those of the controls (0.63+0.04, 7.6+0.7 pM). study. One explanation is that the increase in NOis sequestered CGMP,NO2~and NO3~did not correlate with the number of in a closed compartmentof the brain and is not reflected to the white blood cells in CSF or the age of the subjects in any of the CSFspace. This is not the case with GBSin which the de- groups studied (-0.305<r<0.259). There was no correlation myelinating lesion is exposed to the CSF space. To our know- between CGMPand NO2" or NO3" (r=-0.006, -0.025, respec- ledge, there is no study on NOin GBSalthough NO-inducible Internal Medicine Vol. 34, No. 8 (August 1995) 735 Ikeda et al 30- i.o- ; e 20- à" : ± ' ' : . I | ! -^ ~"~ -*- t * ° 10- ^r~ s : s * » t à" à" à" t à" T t T 0.0-' ' ' ' ' ' ' C BM AM MS GBS C BM AM MS GBS A 20- B C I i : » -r- Figure 1.
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