Is there a role for nitric oxide activity in cervicogenic headache?

Cervicogenic headache (CEH) is a unilateral headache that can be provoked by neck movement, awkward head positions or pressure on tender points in the neck. The mechanisms underlying the stimulation of pain in CEH are not clearly known. In this study, we measured serum nitrate and nitrite levels as an index of nitric oxide (NO) activity in 15 patients with CEH during headache and headache-free periods and in 15 healthy controls. Total nitrate+nitrite levels were found to be higher in CEH patients during headache periods than in healthy controls (20.7+/-3.8 micromol/l vs 14.4+/-3.6 micromol/l, p<0.001), but not in CEH patients during headache-free periods (16.1+/-2.2 micromol/l) compared with the controls (p>0.05). In the patients with CEH, serum total nitrate+nitrite levels were found to be higher during headache periods than during headache-free periods (p=0.001). It can thus be hypothesized that the changes observed are a cause of the attack rather than a consequence of the disease process.     

Central nervous system nitric oxide formation in cerebral systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an inflammatory disease in which up to two thirds of the patients present neurological symptoms. The diagnosis of the disease is based on clinical findings and the presence of autoantibodies, and the pathogenesis is unclear. The purpose of this study was to determine if the pathogenesis was partly mediated via nitric oxide (NO) formation. Cerebrospinal fluid (CSF) samples from 15 patients with cerebral SLE were analyzed for the NO metabolites nitrite and nitrate using capillary electrophoresis. The severity of neurological symptoms was scored by dividing the patients into two groups with either mild or moderate/severe CNS involvement. All patients with cerebral SLE showed increased levels of NO metabolites. In CSF, there was a relationship between signs of NO production and clinical results showing that increased levels of nitrite and nitrate were associated with more severe neurological symptoms. These findings may shed new light on the pathogenesis of cerebral SLE, and analysis of nitrate and nitrate may prove to be of value in monitoring the activity of the disease.     

Nitric oxide metabolites and interleukin-6 in cerebrospinal fluid from multiple sclerosis patients

Interleukin-6 (IL-6) and nitric oxide (NO) are implicated in the pathology of multiple sclerosis (MS). We have investigated the levels of these mediators in the cerebrospinal fluid (CSF) from 50 patients with MS and 23 control subjects. Mean CSF IL-6 level was higher in the total MS group in comparison with controls, but not significantly, whilst the difference between patients with stable MS and controls reached the level of statistical significance. Mean CSF nitrite/nitrate level was significantly higher in the total MS group compared with the control group, as well as in active MS patients versus controls. There was significant difference neither in the mean CSF IL-6 nor in nitrite/nitrate levels between active and stable MS patients. Interestingly, we observed a significant negative correlation between IL-6 and nitrite/nitrate levels in the CSF in the total MS group. Such a trend existed in both subgroups with active and stable MS, but without reaching the level of statistical significance. Our data further support the involvement of IL-6 and NO in ongoing pathological processes in MS, suggesting their potential interplay within the central nervous system in this disease.     

NOx (nitrite/nitrate) in cerebral spinal fluids obtained from patients with influenza-associated encephalopathy

It has become evident that the number of patients with a new type of influenza-associated encephalopathy is increasing in Japan. Nitric oxide (NO), a simple free radical gas, elicits a wide range of physiological and pathophysiological effects. We measured the nitrite/nitrate (NO x ) levels in cerebral spinal fluid obtained from patients with influenza-associated encephalopathy in order to evaluate the correlation between the NO production and the process of influenza-associated encephalopathy. Fifteen children were enrolled, aged from 1 to 9 years. As control we used 14 cerebral spinal fluids obtained from patients with urinary tract infection, respiratory infection or mumps meningitis without any sequela. NO 3 in influenza-associated encephalopathy was significantly higher than that of control group. On the other hand NO 2 was not significantly higher than that of control group. In particular, 4 out of 5 fatal cases revealed high NO 2 or NO 3. One case having normal levels in NO 2 and NO 3 showed that NH 3 was high. These results revealed that NO plays a role in influenza-associated encephalopathy through indirect effects of NO.     

Investigation of neuroprotective effect of dexamethasone by using nitric oxide and leukocyte levels in experimental head trauma

The objective of the present study was to determine the levels of nitric oxide (NO) and white blood cells (WBCs), which are assumed to play a role in secondary cerebral damage by increasing to pathological levels during cranial trauma, and to investigate the neuroprotective effect of dexamethasone on NO and WBC levels in experimental cranial trauma. For this purpose, adult Sprague-Dawley male rats were used. Blood NO and WBC levels were investigated in one group of non-trauma rats (control group, n = 10) after 6 h; in a group of rats with experimental post-cranial trauma (trauma group, n = 10) after 6 and 24 h; and in a third group of rats with experimental cranial trauma, intraperitoneally injected with 10 mg/kg dexamethasone after 1 and 12 h (trauma + dexamethasone group, n = 10), WBC and NO levels were measured after 6 and 24 h. Determination of NO levels was carried out by assaying serum nitrite and nitrate levels. The increases in post-trauma serum NO (nitrite and nitrate) and WBC levels were statistically significant for the trauma and trauma + dexamethasone groups compared to controls. There was no significant difference between serum NO and WBC levels in rats in the trauma + dexamethasone and those in the trauma group. The study demonstrated no significant inhibition of NO and WBC levels by dexamethasone, a drug used for its anti-edema and anti-inflammatory effects and its influence on membrane stabilization and in avoiding oscillation stress. In the present study, dexamethasone was found to be ineffective in decreasing NO and WBC levels to avoid secondary cerebral damage after cranial trauma.     

新生儿缺氧缺血性脑病血清NO2／NO3和cGMP的改变

目的研究新生儿缺氧缺血性脑病（HIE）血清一氧化氮（NO）的变化及其临床意义。方法采用镀铜镐还原法和放射免疫法检测48例HIE患者血清NO2／NO3和cGMP的含量。结果新生儿HIE血清中NO2／NO3和cGMP的含量明显高于对照组（P＜0．01），治疗后患者血清中NO2／NO3和cGMP的含量较治疗前明显减低（P＜0．05）。结论NO参与了新生儿HIE的发病过程，检测血清NO的含量有助于判断患者的病情。提示临床开发和应用NO生成抑制剂可能有助于新生HIE的治疗。     

CEREBROSPINAL FLUID NITRITE AND MALONDIALDEHYDE LEVELS IN PATIENTS WITH MOTOR NEURON DISEASE

Nitric oxide (NO) mediated oxidative damage may be involved in the pathogenesis of neuronal degeneration in motor neuron disease (MND). The present study was undertaken to evaluate the role of NO and oxidative stress in MND by estimating nitrite and malondialdehyde (MDA) levels in the cerebrospinal fluid (CSF) in 22 patients of MND and 20 control subjects suffering from neurological disorders not known to affect NO metabolism. There was no significant change in the CSF nitrite and MDA levels in MND. The nitrite and MDA levels did not have any significant correlation with age, duration of illness, or severity of disease.­ Univariate analysis of the clinical features in patients with MND and the nitrite levels revealed that two patients with a positive family history had significantly higher CSF nitrite levels as compared to those with a negative family history. There was no correlation between the CSF nitrite and MDA levels. Results of the present study did not indicate significant alterations in the MDA and NO levels in the CSF of MND patients. However, involvement of NO in MND with positive family history is suggested by the results obtained.­     

Cerebrospinal fluid nitrite and malondialdehyde levels in patients with motor neuron disease

Nitric oxide (NO) mediated oxidative damage may be involved in the pathogenesis of neuronal degeneration in motor neuron disease (MND). The present study was undertaken to evaluate the role of NO and oxidative stress in MND by estimating nitrite and malondialdehyde (MDA) levels in the cerebrospinal fluid (CSF) in 22 patients of MND and 20 control subjects suffering from neurological disorders not known to affect NO metabolism. There was no significant change in the CSF nitrite and MDA levels in MND. The nitrite and MDA levels did not have any significant correlation with age, duration of illness, or severity of disease. Univariate analysis of the clinical features in patients with MND and the nitrite levels revealed that two patients with a positive family history had significantly higher CSF nitrite levels as compared to those with a negative family history. There was no correlation between the CSF nitrite and MDA levels. Results of the present study did not indicate significant alterations in the MDA and NO levels in the CSF of MND patients. However, involvement of NO in MND with positive family history is suggested by the results obtained.     

Raised cerebrospinal fluid nitrite and nitrate levels in patients with multiple sclerosis: no correlation with disease activity

A growing body of evidence implicates excessive generation of nitric oxide (NO) within the central nervous system (CNS) in multiple sclerosis (MS). The aim of our study is to analyse nitrite and nitrate as end products of NO in the cerebrospinal fluid (CSF) from MS patients and correlate the concentrations with clinicol characteristics of the disease. CSF nitrite and nitrate concentrations were measured after reduction of nitrate, by Griess reaction, in 105 MS potients, 27 patients with non-inflammatory neurological disorders (NIND) and 13 individuals without neurological disorder (Co). Mean CSF nitrite and nitrate concentrations were significantly higher in patients with MS and NIND compared with the Co patients (9.44 and 8.68, respectively, versus 6.85 microM; P=0.0001 and P=0.031, respectively). There was no significant correlation between CSF nitrite and nitrate concentrations and activity, phase, severity and duration of MS. Our data are in agreement with the results of previous studies which have demonstrated raised concentrations of CSF NO metabolites in MS patients, providing further evidence for NO involvement in MS. The lack of correlation between NO metabolites and disease activity speaks in favour of the possible dual role of NO, as both immunoregulatory and pro-inflammatory molecule, in the pathogenesis of MS.     

Cerebrospinal fluid nitrite/nitrate correlated with oxyhemoglobin and outcome in patients with subarachnoid hemorrhage

The findings of various studies reporting temporal changes in CSF total nitrite/nitrate (NOx) levels after subarachnoid hemorrhage (SAH) vary considerably. The study group comprised 10 patients with SAH and 10 control subjects. Total nitrite/nitrate concentration was measured by a vanadium-based assay with the colorimetric Griess reaction. CSF oxyhemoglobin level was assessed by spectrophotometry. After an initial peak (22.6+/-10.1 microM) within first 24 h after SAH, CSF NOx decreased gradually during the period of observation. There was a significant correlation between CSF concentrations of NOx and OxyHb in the entire observation period (R=0.87, p<0.001). When the impact of bleeding into CSF was considered, patients with very good outcome [Glasgow Outcome Scale (GOS)=5] had significantly lower CSF NOx (11.1+/-1.3 microM) than those with worse outcome (GOS<5) (21.8+/-11.2 microM, p<0.01). In conclusion, this study demonstrates that after aneurysm rupture CSF NOx levels correlate with OxyHb. We suggest this as a novel interpretation of other variable findings in relation to NO metabolites in the central nervous system (CNS) post SAH, and hence it could usefully be incorporated into the planning of future studies, correlating NOx with clinical outcome.     

Serum and urine nitrate and nitrite are not reliable indicators of intrathecal nitric oxide production in acute brain injury

This study examined the correlation between nitric oxide (NO) metabolites in the three major body fluid compartments and assessed performance of newly described vanadium-based assay for simultaneous detection of nitrite and nitrate (NO(x)) in human samples. Vanadium reduces nitrate to nitrite, which can be measured after a colorimetric reaction with Griess reagents.Cisternal cerebro spinal fluid (CSF), serum and urine samples from 10 patients with acute brain injury (ABI) were compared to control subjects. Significantly higher CSF NO(x) levels were found in brain injury patients compared to control patients (19.7+/-13.7 vs. 6.5+/-2.3 microM; p=0.01), which persisted for 10-day period of observation. The serum and urine levels of NO(x) on admission were not statistically different (42.8+/-28.2 microM; 584.1+/-337.8 micromol/g Cr, respectively) from controls (36.8+/-14.8 microM; 819.7+/-356.0 micromol/g Cr), but tended to decrease during the disease course reaching the lowest level on day 6 (serum: 19.3+/-8.4 microM, urine: 300.4+/-111.9 micromol/g Cr). CSF levels of NO(x) correlated moderately with those in serum (p=0.001, R=0.5). Serum NO(x) concentrations correlated weakly with urine levels (p=0.04, R=0.3). There was no significant correlation between CSF NO(x) and urine NO(x) levels.In conclusion, patients suffering brain injury had increased NO(x) concentrations in CSF, which remained independent from other body fluid compartments. Serum and urinary NO(x) levels cannot be used as a reliable index to assess intrathecal NO production.     

Possible role of nitric oxide in postoperative ileus: a comparative study

In the present study, the possible involvement of nitric oxide (NO) in the pathogenesis of postoperative ileus was investigated indirectly by measuring nitrate, a stabile metabolite of NO. Plasma levels and 24-h urinary excretion of nitrate and nitrite were determined in the peri-operative period in three different groups of patients undergoing surgery: group 1 (LT, n=11) underwent a laparotomy, group 2 (LS, n=12) underwent a laparoscopic procedure, whereas group 3 underwent an extra-abdominal procedure (EA, n=9). Duration of postoperative ileus was assessed clinically using first occurrence of flatus and defaecation as the end of the period of ileus. Postoperative ileus lasted significantly longer in the LT group (first flatus after 3.0 [3.0-4.0] days) compared with the LS (1.0 [1.0-2.0] days) and EA (1.0 [1.0-3.0] days) groups. Urinary nitrate excretion increased significantly in the LT and EA groups during the first 24 h after surgery (from 797.0 [214.0-810.0] and 551.5 [438.3-1215.8] to 2079.0 [889.0-4644.0] and 1102.5 [315.3-1238. 0] micromol/24 h, median [IQR]), but normalized before the end of postoperative ileus. Plasma levels of nitrate were unchanged after surgery, whereas CRP levels were significantly increased in all groups (LT > LS=EA). In the first 24 h following surgery, urinary nitrate excretion is increased, suggesting increased endogenous synthesis of NO postoperatively. As no correlation was found between urinary nitrate excretion and duration of postoperative ileus, we conclude that assessment of nitrate has no value in predicting clinical outcome after surgery.     

Nitric oxide metabolites in CSF of patients with MS are related to clinical disease course

In this study, we have analyzed the stable metabolites of nitric oxide (NO), nitrite and nitrate, in the CSF of patients with MS, lymphocytic meningitis, and in healthy control subjects. Patients with MS with an active disease course exhibited increased CSF nitrite levels compared with patients with stable MS and healthy control subjects, whereas CSF nitrate levels did not differ between these groups. High CSF levels of both metabolites were seen in patients with meningitis. These data indicate that CSF nitrite levels may reflect clinical disease activity in MS.     

The importance of cytokines, chemokines and nitric oxide in pathophysiology of migraine

The certain etiology migraine is unknown. The study was aimed at determining to the efficiency of cytokines, chemokines and nitric oxide (NO) to the pathophysiology of migraine. The levels of cytokines, chemokines and NO in serum of 25 patients with migraine during attacks and attack-free periods and 25 healthy controls were investigated. The levels of cytokines and chemokines were determined by enzyme-linked immunosorbent assay. NO concentrations were determined by a nitrate/nitrite colorimetric assay kit. In attack groups, IL-10 levels were found higher than in attack-free groups and healthy controls (p<0.05). IL-6 levels in migraine patients were significantly higher than in healthy controls. The levels of RANTES were high in attacks groups. There was an increase NO concentrations in migraine attacks. The study's results reflect that the etiology of migraine is multifactorial and probably related to immunological changes.     

Plasma nitrate values in patients with obsessive-compulsive disorder

Recently there has been increasing evidence that free oxygen species may play an important role in the pathophysiology of various neuropsychiatric disorders. The present study was performed to assess the changes in plasma nitric oxide (NO) levels in patients with obsessive-compulsive disorder (OCD) compared to age- and sex-matched normal controls. Twenty-three patients with OCD and 23 healthy volunteers were included in the study. NO values were determined in the plasma of normal healthy controls and the OCD patients. Plasma nitrate levels in OCD patients were significantly higher than those in controls and were significantly and positively correlated with Yale-Brown Obsession Compulsion Scale scores but not related to age or to the duration of illness. These findings indicated a possible role of increased NO may be relevant to the pathophysiology of OCD.     

Low concentration of nitrite and nitrate in the cerebrospinal fluid from schizophrenic patients: a pilot study

Some evidence suggests a dysfunctional nitric oxide (NO) system in the brain of schizophrenic subjects. We measured the concentrations of the stable metabolites of NO, nitrite, and nitrate in the cerebrospinal fluid (CSF) from schizophrenic and control patients with other neurological disorders and found lowered levels in the schizophrenic group as compared with the control group. This finding supports the hypothesis of a NO system reduction in the brain of schizophrenic subjects.     

Increased nitric oxide products in CSF in primary progressive MS may reflect brain atrophy

Because nitric oxide (NO) is a putative mediator of oligodendrocyte damage in the primary progressive form of MS (PPMS), the authors analyzed the levels of NO oxidation products in CSF and plasma from 25 patients with PPMS and 15 controls. The levels of nitrite + nitrate (NOx) in CSF were fourfold higher in patients with PPMS than in controls (p < 0.001), whereas the concentrations in plasma were similar. These data suggests involvement of NO in nervous tissue damage in PPMS.     

Increased nitric oxide radicals in postmortem brain from patients with schizophrenia

Alterations in antioxidant status in schizophrenia suggest free radical-mediated neurotoxicity; this finding can be a consequence of increased free radical production. There are multiple pathways to excess free radical generation and subsequent oxidative stress. One such pathway is the formation of peroxynitrite by a reaction of nitric oxide (NO) and superoxide radical. NO is formed from L-arginine by nitric oxide synthase (NOS). A constitutive cytosolic isoform, neuronal NOS (nNOS), appears to be fairly stable in the postmortem brain tissues. Utilizing a sensitive fluorometric assay, NO levels were measured by its stable metabolites, nitrate and nitrite, in the caudate region of postmortem brain tissues from patients and control subjects. In the human brain, NO is metabolized primarily in the form of nitrate. A significantly increased level of NO was found in schizophrenia patients (241 +/- 146 pmol/mg dry weight, n = 18) than was found in those of normal (142 +/- 65 pmol/mg dry weight, n = 20) and psychiatric controls without schizophrenia (125 +/- 83 pmol/mg dry weight, n = 16) (analysis of covariance [ANCOVA], F = 6.446, df = 2,51, p = 0.003). These findings were independent of age, brain weight, postmortem interval (PMI), sample storage time, or cigarette smoking. Elevated NO levels in the brains of schizophrenia patients lend further support for the free radical pathology in schizophrenia.     

Nitrite,nitrate and cGMP in the cerebrospinal fluid in degenerative neurologic diseases

Summary To investigate whether nitric oxide (NO) plays a role in degenerative neurologic disease (DND), we measured nitrite, nitrate and cyclic GMP in cerebrospinal fluid (CSF) samples from patients with Parkinson's disease (PD), spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS). We found no significant change in CSF nitrite, nitrate or cyclic GMP in patients with any DND compared with control values. These results suggest that NO production is preserved in PD, SCA and ALS.     

Effect of exercise training on oxidized LDL-mediated platelet function in rats

This study investigates how exercise training affects Oxidized LDL (Ox-LDL) mediated-platelet activation. Five-week-old male Wistar rats were assigned to either control or trained groups. Trained rats were treadmill-trained for 10 weeks after familiarization. The following measurements were taken in both control and trained groups: Ox-LDL-mediated platelet aggregability and [Ca2+]i, plasma and platelet-derived nitric oxide (NO) metabolite (nitrite plus nitrate) levels, and antiaggregating activity of NO derived from endothelial cells. Based on those measurements, major findings in this study can be summarized as follows: 1) the trained group had a higher plasma -NO metabolite level than the control group; 2) the trained group had a lower platelet aggregability and [Ca2+]i elevation and a higher platelet derived-NO metabolite level than the control group; 3) the trained group had lower Ox-LDL-potentiated platelet aggregability and [Ca2+]i elevation and Ox-LDL-attenuated NO metabolite in platelet than the control group; 4) treating the platelet with L-arginine inhibited Ox-LDL-potentiated platelet activation in both control and trained groups; 5) Ox-LDL enhances platelet aggregation directly although impairing NO bioactivity but not guanylate cyclase activity in both control and trained groups. Results in this study demonstrate that exercise training decreases Ox-LDL-potentiated platelet activation most likely by enhancing platelet-derived NO release.