Nitric Oxide Production In Brain Research Articles

Buchholzia coriacea seed extract attenuates mercury-induced cerebral and cerebellar oxidative neurotoxicity via NO signaling and suppression of oxidative stress, adenosine deaminase and acetylcholinesterase activities in rats.

Objective:Mercury (Hg) is a classic cumulative neurotoxicant implicated in neuronal deficit via oxidative damage and inflammatory responses. We sought to investigate whether Buccholzia coriacea seed methanol extract (BCSE) would modulate oxidative neurotoxicity induced by Hg in rats. Materials and Methods:Rats were orally treated with BCSE (200 or 400 mg/kg body weight of rat) for 28 days, while Hg was administered from day 15 to day 28. After sacrifice, antioxidant enzyme activities, reduced glutathione (GSH), nitric oxide (NO), malondialdehyde (MDA), and acetylcholinesterase (AchE) and adenine deaminase (ADA) activities were evaluated in the cerebrum and cerebellum of rats. Results:Mercury induced significant depressions in catalase (CAT) and glutathione peroxidase (GPx) activities and GSH levels, whereas levels of NO and activities of AchE and ADA markedly increased. The histopathology of the brain tissues confirmed these changes. In contrast, BCSE administration prominently modulated the brain NO production and reversed the Hg-induced biochemical alterations comparable to normal control. Conclusion:Methanol extract of B. coriacea seeds protects the cerebrum and cerebellum against Hg-induced brain damage via its antioxidant and NO modulatory actions.

Olfactory Dysfunctions and Decreased Nitric Oxide Production in the Brain of Human P301L Tau Transgenic Mice.

Different patterns of olfactory dysfunction have been found in both patients and mouse models of Alzheimer's Disease. However, the underlying mechanism of the dysfunction remained unknown. Deficits of nitric oxide production in brain can cause olfactory dysfunction by preventing the formation of olfactory memory. The aim of this study was to investigate the behavioral changes in olfaction and alterations in metabolites of nitric oxide, nitrate/nitrite concentration, in the brain of human P301L tau transgenic mice. The tau mice showed impairments in olfaction and increased abnormal phosphorylation of Tau protein at AT8 in different brain areas, especially in olfactory bulb. We now report that these olfactory deficits and Tau pathological changes were accompanied by decreased nitrate/nitrite concentration in the brain, especially in the olfactory bulb, and reduced expression of nNOS in the brain of tau mice. These findings provided evidence of olfactory dysfunctions correlated with decreased nitric oxide production in the brain of tau mice.

Chronic exposure to imidacloprid induces inflammation and oxidative stress in the liver & central nervous system of rats

Imidacloprid is the most important example of the neonicotinoid insecticides known to target the nicotinic acetylcholine receptor (nAChR) in insects, and potentially in mammals. In the present study, oxidant and inflammatory responses to chronic exposure of imidacloprid was studied in rats. Wistar rats were randomly allocated into two groups as control and imidacloprid-exposed group (n=10rat/each group). 1mg/kg/BW/day imidacloprid was administrated orally by gavage for 30days. After exposure, rats were euthanized and liver and brain samples were surgically removed for analyses. Imidacloprid application caused a significant increase in nitric oxide production in brain (p<0.05) and liver (p<0.001). The quantitative analyses of mRNA confirmed the finding that imidacloprid induced the mRNA transcriptions of the three isoforms of nitric oxide synthases (iNOS, eNOS, nNOS) in brain and two isoforms (iNOS, eNOS) in the liver. Exposure to imidacloprid caused significant lipid peroxidation in plasma, brain (p<0.001) and liver (p<0.003). While the superoxide-generating enzyme xanthine oxidase activity was elevated in both tissues (p<0.001), myeloperoxidase activity was increased only in the liver (p<0.001). Antioxidant enzyme activities showed various alterations following exposure, but a significantly depleted antioxidant glutathione level was detected in brain (p<0.008). Evidence of chronic inflammation by imidacloprid was observed as induction of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-12 and IFN-γ in the liver and brain. In conclusion, chronic imidacloprid exposure causes oxidative stress and inflammation by altering antioxidant systems and inducing pro-inflammatory cytokine production in the liver and central nervous system of non-target organisms.

Involvement of glutamate, oxidative stress and inducible nitric oxide synthase in the convulsant activity of ciprofloxacin in mice

This study investigated the potential convulsive activity of ciprofloxacin in mice and the possible mechanism(s) of this activity. Intraperitoneal (i.p.) administration of ciprofloxacin into mice resulted in convulsive seizures in a dose-dependent manner. The clonic median convulsant dose (CD50) of ciprofloxacin in mice was increased by pretreatment with dizocilpine, alpha-lipoic acid or aminoguanidine, not changed by pretreatment with 7-nitroindazole and decreased by pretreatment with l-arginine and fenbufen. The increase in nitric oxide (NO) production and malondialdehyde (MDA) level as well as the decrease in intracellular reduced glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity induced by the estimated clonic CD50 of ciprofloxacin in mice brain was inhibited by pretreatment with dizocilpine, alpha-lipoic acid or aminoguanidine. These biochemical alterations were not changed by pretreatment with 7-nitroindazole but enhanced by pretreatment with l-arginine. The elevation induced by the clonic CD50 of ciprofloxacin in brain glutamate level was not changed by pretreatment with MK-801, alpha-lipoic acid, aminoguanidine or l-arginine. Combined treatment of mice with fenbufen and ciprofloxacin produced elevation of brain NO production and glutamate and MDA levels as well as inhibition of brain intracellular GSH level and GSH-Px activity. In addition, i.p. administration of the clonic CD50 of ciprofloxacin produced an increase in inducible but not in neuronal NO synthase mRNA and protein expressions in mice brain. These results suggest that elevation of brain glutamate levels with consequent oxidative stress and increase in the expression and activity of brain inducible NO synthase may play a pivotal role in ciprofloxacin-induced convulsive seizures.

Effects of Flaxseed Oil on Lead Acetate-Induced Neurotoxicity in Rats

It is well known that chronic exposure to lead (Pb(+2)) alters a variety of behavioral tasks in rats and mice. Here, we investigated the effect of flaxseed oil (1,000mg/kg) on lead acetate (20mg/kg)-induced brain oxidative stress and neurotoxicity in rats. The levels of Pb(+2), lipid peroxidation, nitric oxide (NO), and reduced glutathione (GSH) and the activity of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione-S-transferase (GST), and glutathione peroxidase (GPx) were determined in adult male albino rats. The level of Pb(+2) was markedly elevated in brain and blood of rats. This leads to enhancement of lipid peroxidation and NO production in brain with concomitant reduction in GSH, CAT, SOD, GR, GST, and GPx activities. These findings were associated with DNA fragmentation. In addition, lead acetate induced brain injury as indicated by histopathological changes of the brain. Treatment of rats with flaxseed oil resulted in marked improvement in most of the studied parameters as well as histopathological features. These findings suggest to the conclusion that flaxseed oil significantly decreased the adverse harmful effects of lead acetate exposure on the brain as well as Pb(+2)-induced oxidative stress.

Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats

Baroreflex sensitivity is disturbed in many people with cardiovascular diseases such as hypertension. Brain deficiency of nitric oxide (NO), which is synthesized by NO synthase (NOS) in the citrulline-NO cycle (with argininosuccinate synthase (ASS) activity being the rate-limiting step), contributes to impaired baroreflex. We recently showed that a decapeptide isolated from Bothrops jararaca snake venom, denoted Bj-PRO-10c, exerts powerful and sustained antihypertensive activity. Bj-PRO-10c promoted vasodilatation dependent on the positive modulation of ASS activity and NO production in the endothelium, and also acted on the central nervous system, inducing the release of GABA and glutamate, two important neurotransmitters in the regulation of autonomic systems. We evaluated baroreflex function using the regression line obtained by the best-fit points of measured heart rate (HR) and mean arterial pressure (MAP) data from spontaneously hypertensive rats (SHRs) treated with Bj-PRO-10c. We also investigated molecular mechanisms involved in this effect, both in vitro and in vivo. Bj-PRO-10c mediated an increase in baroreflex sensitivity and a decrease in MAP and HR. The effects exerted by the peptide include an increase in the gene expression of endothelial NOS and ASS. Bj-PRO-10c-induced NO production depended on intracellular calcium fluxes and the activation of a G(i/o)-protein-coupled metabotropic receptor. Bj-PRO-10c induced NO production and the gene expression of ASS and endothelial NOS in the brains of SHRs, thereby improving baroreflex sensitivity. Bj-PRO-10c may reveal novel approaches for treating diseases with impaired baroreflex function.

The % Tetrahydrobiopterin (BH4) and Serine 1177 Phosphorylation Is Reduced in Sickle Transgenic Mice.

Tetrahydrobiopterin (BH4) is an essential co-factor of nitric oxide synthase (NOS), the enzyme that generates nitric oxide (NO) from arginine and oxygen. NO plays an essential role in maintaining vascular tone and endothelial function, reducing levels of adhesion molecules and platelet aggregation, and reducing inflammation; all of which are critical in sickle cell disease (SCD). In addition to BH4, arginine, calmodulin, intracellular Ca++ levels, hsp90, phosphorylation at serine 1177 and threonine 495, and monomer/dimer equilibrium have all been shown to modulate NO and superoxide production by eNOS. Arginine levels are decreased in plasma in SCD. We have demonstrated that plasma arginine is reduced in sickle transgenic mice and that arginine supplementation partially restores both red cell and vascular function. Channon et al have demonstrated that, in atherosclerosis and diabetes, enhanced superoxide production is associated with BH4 depletion; superoxide can interfere with both NO production and, by reacting with NO, with bioavailability. We hypothesized that a similar depletion of BH4 occurs in SCD and that treatment protective of tissue BH4 levels may interrupt the cycle of polymerization, vaso-occlusion and inflammation that is the origin of pathology in SCD. We report here depletion of BH4 in tissue and plasma of several lines of sickle transgenic mice and the effect of hypoxia on % BH4 and serine 1177 phosphorylation in NY1DD mice, a mild sickle transgenic mouse that becomes more severe when exposed to hypoxia. Only BH4 is active as a NOS cofactor, the oxidized forms BH2 and biopterin (B) are inactive. Results are presented as %BH4 (BH4/(BH4+BH2+B)). We find that %BH4 is the same in C57BL and NY1DD mice under room air in plasma and brain. After exposure to 4 days of hypoxia (8% O2), % BH4 is reduced from 75.7%±3.8% to 53.7%±3.8% in plasma, p<0.004 and from 82.0%±3.7% to 68.7%±3.7% in brain, p<0.006. At the same time total biopterin (BT= BH4+BH2+B) increased in plasma, but remained constant in brain. We also measured eNOS phosphorylated at serine 1177 in brain in NY1DD mice. We find that the % phosphorylation decreases from 45.0%±7.9% to 28.3%±7.3%, p<0.007 after 4 days of hypoxia, but that at the same time total eNOS and total nNOS nearly doubled. BERK mice express exclusively HbS and, under normoxia, we found decreased %BH4 in brain in BERK mice (58%±3.3% vs 76.7%±3.0% for C57, p<0.003) with constant BT. In red cells of BERK mice, the %BH4 is about the same as C57BL (81.7% vs 76.7%, respectively), but BT doubled from 124 to 257, p>0.01. In conclusion, increased total expression of eNOS and nNOS and decreased %BH4 with decreased % phosphorylation at serine 1177 of eNOS suggest that NO production in brain in NY1DD mice after hypoxia may be severely compromised. Percent BH4 is also reduced in brain of BERK mice under normoxia, which suggests that BH4 is reduced in more severe mice under room air. Plasma and red cell %BH4 and BT do not have a simple relation to tissue levels, but do respond to pathology and may be the only readily measurable variable in human studies. The multiple pathways for disregulation of NOS in SCD involve not only NO scavenging by plasma free Hb and arginine deficiency, but also reduced bioavailability of BH4.

Spermine reduces infarction and neurological deficit following a rat model of middle cerebral artery occlusion: a magnetic resonance imaging study

The role of nitric oxide (NO) in post-ischemic cerebral infarction has been extensively examined, but few studies have investigated its role on the neurological deficit. In the present study, we investigated the effect of spermine on the temporal evolution of infarct volume, NO production and neurological deficit using magnetic resonance imaging in a model of permanent focal cerebral ischemia in rats. Spermine given at 10 mg/kg 2 h after ischemia reduced the infarct volume by 40% and abolished brain NO production and improved the neurological score 24 h, 48 h and 72 h after ischemia. Spermine also reduced the neurological deficit as evaluated by rotamex, grip strength and neurological severity score tests.

L-NAME reduces infarction, neurological deficit and blood–brain barrier disruption following cerebral ischemia in mice

The role of nitric oxide (NO) in the development of post-ischemic cerebral infarction has been extensively examined, but fewer studies have investigated its role in other outcomes. In the present study, we first determined the temporal evolution of infarct volume, NO production, neurological deficit and blood–brain barrier disruption in a model of transient focal cerebral ischemia in mice. We then examined the effect of the nonselective NO-synthase inhibitor N ω-nitro- l-arginine-methylester ( l-NAME). l-NAME given at 3 mg/kg 3 h after ischemia reduced by 20% the infarct volume and abolished the increase in brain NO production evaluated by its metabolites (nitrites/nitrates) 48 h after ischemia. l-NAME with this protocol also reduced the neurological deficit evaluated by the grip test and decreased by 65% the extravasation of Evans blue, an index of blood–brain barrier breakdown. These protective activities of l-NAME suggest that NO has multiple deleterious effects in cerebral ischemia.

Poster Sessions CP13: Hypoxia, Ischemia and Oxidative Stress. Changes of brain nitric oxide production in experimental cerebral ischemia

In order to study the role of nitric oxide (NO) in ischemic brain injury. Global cerebral ischemia was established in SD rats by modified Pulsinelli's method. The activities of constitutive nitric oxide synthase (cNOS), inducible NOS (iNOS), neuronal NOS (nNOS), nitrite (NO2) and cyclic GMP in cerebral cortex, hippocampus, striatum and cerebellum at different time intervals were measured by radioimmunoassy, NADPH‐d histochemistry and fluorometry methods. The results showed that the activities of cNOS increased at 5 min in four regions and decreased in cortex, hippocampus and striatum at 60 min, in cerebellum at 15 min iNOS increased in cortex and striatum at 15 min, in hippocampus and cerebellum at 10 min, and persisted to 60 min. The expression of nNOS increased after 5 min ischemia in cortex, striatum and hippocampus, and return to normal at 30–60 min. The NO2 and cGMP also increased after 5–15 min ischemia and returned to normal after 30–60 min ischemia. These results indicated that the NO participated in the pathogenesis of cerebral ischemia injury and different types of NOS play different role in the cerebral ischemia injuries. Selected specific NOS inhibitors to decreased the excessive production of NO at early stage may help to decrease the ischemic injury.

Localization and Role of Nitric Oxide Synthase and Endogenous Nitric Oxide Synthase Inhibitors in the Rabbit Lower Urinary Tract

We investigated the possible role of endogenous methylarginine derivatives, such as NG-monomethyl-L-arginine (L-NMMA), asymmetrical NG, NG-dimethyl-L-arginine (ADMA) and symmetrical NG, N'G-dimethyl-L-arginine (SDMA), for regulating nitric oxide synthase in the rabbit lower urinary tract. Strips of detrusor, trigone and proximal urethra were processed for the determination of endogenous methylarginines and L-arginine by automated high performance liquid chromatography. We also compared nitric oxide synthase activity and nitric oxide mediated functional responses to electrical field stimulation in the 3 regions. Nitric oxide synthase activity was measured by determining the conversion of [3H] L-arginine to [3H] L-citrulline. L-NMMA, ADMA and SDMA were detectable by high performance liquid chromatography in the detrusor, trigone and proximal urethra. Electrical field stimulation induced nitric oxide mediated prominent relaxation in the trigone and proximal urethra, while no relaxation response was observed in the detrusor. Exogenously applied 1 to 100 microM. L-NMMA and 1 to 100 microM. ADMA but not 100 microM. SDMA dependently inhibited Ca2+ dependent nitric oxide synthase activity in all regions, and electrical field stimulation induced relaxation in the trigone and proximal urethra. Inhibition with L-NMMA and ADMA was blocked in the presence of 3 mM. L-arginine but not by 3 mM. D-arginine. Three methylarginines and nitric oxide synthase are localized throughout the rabbit lower urinary tract. Endogenous L-NMMA and ADMA may be involved in regulating nitric oxide biosynthesis of the micturition reflex in the normal or disease state.

Nitric oxide and reactive nitrogen intermediates during lethal and nonlethal strains of murine malaria.

The virulence of Plasmodia depends partly on the strain of parasite and partly on the host. In this study, Plasmodium berghei N/13/1A/4/203 caused the death of mice, whereas Plasmodium chabaudi chabaudi AS was not lethal. Current opinion is that nitric oxide (NO) and other reactive nitrogen intermediates (RNI) are produced in several host organs during malaria to resist infection or produce tissue damage. NO and RNI production in blood or plasma, brain, liver and spleen in MF1 mice was investigated during P. berghei and P. c. chabaudi infection, in order to help determine whether changes in NO production are beneficial or detrimental to the host in vivo. NO production was measured both directly and indirectly as nitrites and nitrates, to represent RNI. No changes in blood NO were detected in P. berghei infected mice, but increases were observed in brain, liver and spleen. In P. c. chabaudi infected mice, rises in NO concentration were observed in blood and spleen, whereas a decline in liver NO was seen, but there were no changes in brain. Liver contained the highest concentration of RNI, but increasing concentrations were seen in both plasma and spleen in both P. berghei and P. c. chabaudi infected mice. These results show that NO and RNI production alters during murine malaria. The changes depend upon the tissue, the day of infection, the degree of parasitaemia, the strain of Plasmodia and the method of measuring NO biosynthesis. Lethal P. berghei induced NO production in the mid and late stages of infection in mice when parasitaemia was high, whereas in nonlethal P. c. chabaudi infection, NO production was increased in the early and late stages when parasitaemia was low. These data are consistent with a role for NO in the protection of the MF1 mouse against Plasmodia. Failure to clear the parasite is associated with evidence of increased NO production in brain and liver, which may contribute to the pathology of malaria, but this hypothesis requires confirmation from other experimental approaches.

Influences of caffeine to nitric oxide production and zonisamide concentration in the brain of seizure-susceptible EL mice.

To investigate changes of nitric oxide (NO) productions and zonisamide (ZNS) concentrations in the brain of seizure-susceptible EL mice given caffeine orally, mice were given caffeine (600 microg/mL) solution ad libitum as a drinking fluid for 1-3 weeks. Nitric oxide production in the brain was determined by measuring levels of nitrite plus nitrate (NOx). The brain NOx levels of mice treated with caffeine for 3 weeks were significantly higher than the control. Seizures in mice treated with caffeine for 2 and 3 weeks were not suppressed by ZNS at a dose of 75 mg/kg. Serum ZNS concentrations of mice with caffeine intake for 1-3 weeks were higher than in untreated mice. Conversely, brain ZNS concentrations of mice with caffeine intake for the same periods were significantly lower than in untreated mice. These results suggested that caffeine influenced brain NO production and ZNS concentrations in the seizure susceptibility of EL mice.

Nitric oxide metabolites, nitrates and nitrites in the cerebrospinal fluid in children with west syndrome

Nitric oxide (NO) has been implicated in the mediation of the neuronal excitotoxic cascade. In order to estimate brain NO production, cerebrospinal fluid (CSF) levels of NO metabolites, nitrates and nitrites (NN x) were measured in 31 children with west syndrome (WS) and in 12 controls. There was no age-related change in the NN x levels during the first year of life. The mean of the NN x levels was significantly higher in patients with WS than in controls (8.43 vs. 5.27 μM; P=0.01). Analysis of the etiological subgroups showed that the patients with a symptomatic etiology of WS had significantly higher NN x levels than controls ( P<0.005) or than the patients with a cryptogenic etiology. The cryptogenic cases, in turn, did not differ from the controls ( P=0.48). Levels of NN x were also significantly higher in children with focal brain abnormalities (infarction, atrophy or previous infection) than in those with other abnormalities or with normal neuroradiological findings ( P<0.005). No correlation was found between the NN x levels and the duration of the symptoms, while paired samples obtained from eight children with WS showed that the NN x levels rose significantly ( P=0.02) within the first 40 days of symptoms. The levels of NN x did not correlate with the CSF levels of neuronal growth factor or with the later decline in mental performance. This study demonstrates that the production of NO can be measured in human epileptic conditions and supports the idea gained from experimental studies that NO is involved in the pathophysiology of epilepsy. However, normal levels of NN x in patients with cryptogenic infantile spasms suggest that an increase in NO production be due to the concomitant neuronal damage rather than seizure activity per se. The findings suggest that there are no age-related changes in the NN x levels during the first year of life, and that children with symptomatic WS have elevated levels of NN x, which rise during the first 40 days of symptoms. Although the NN x levels cannot be used to estimate the duration of symptoms or to predict the prognosis of mental development, they may support the differentiation of symptomatic from cryptogenic etiologies of WS.

Effects of MK-801, dantrolene, and FK506 on convulsive seizures and brain nitric oxide production in seizure-susceptible EL mice

To clarify the role of nitric oxide (NO) in the pathogenesis of seizures in susceptible EL mice, we investigated effects of three drugs potentially related to NO production, MK-801, dantrolene, and FK506, on convulsive seizures and brain NO metabolites (NOx). MK-801 or dantrolene, but not FK506, suppressed convulsive seizures in EL mice; only MK-801 reduced NOx in the brain. Our results suggested involvement of the N-methyl- d-aspartate receptor–channel complex and intracellular calcium mobilization, but not calcineurin, in the convulsions of EL mice.

Markedly elevated nitrate/nitrite levels in the cerebrospinal fluid of children with progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome).

To compare the levels of brain nitric oxide production in patients with PEHO or PEHO-like syndrome and in controls with other neurologic disease. Nitric oxide metabolites, nitrates, and nitrites (NNx), were measured in the cerebrospinal fluid (CSF) of children with PEHO syndrome or PEHO-like syndrome, and in controls with other neurologic diseases. The NNx levels were markedly higher in both PEHO (mean, 48 microM; p < 0.001) and PEHO-like (22 microM; p < 0.003) patients as compared with the controls (6 microM), but did not correlate with age or with brain atrophy or CSF levels of insulin-like growth factor-1 (IGF-1). Our findings suggest that in PEHO syndrome, production of nitric oxide is markedly increased, suggesting that nitric oxide is involved in the pathologic phenomena (i.e., seizures and neurodegeneration) of the disease.

Measurement of total nitric oxide metabolite (NO x−) levels in vivo

The measurement of the total level of nitric oxide (NO) metabolite (NO x −) by microdialysis has recently been used to assess the production of NO in the in vivo brain [D. Luo, S. Knezevich, S.R. Vincent, N-Methyl- d-aspartate-induced nitric oxide release: an in vivo microdialysis study, Neuroscience, 57 (1993), 897–900; K. Ohta, N. Arai, M. Shibata, J. Hamada, S. Komatsumoto, K. Shimazu, Y. Fukuuchi, A novel in vivo system for consecutive measurement of brain nitric oxide production combined with the microdialysis technique, Neurosci. Lett., 176 (1994), 165–168; K. Shintani, S. Kanba, T. Nakai, K. Sato, G. Yagi, R. Kato, M. Arai, Measurement by in vivo microdialysis of nitric oxide release in the rat cerebellum, J. Psychiatr. Neurosci., 3 (1994), 217–221; H. Togashi, K. Mori, K. Ueno, M. Matsumoto, N. Suda, H. Saito, M. Yoshika, Consecutive evaluation of nitric oxide production after transient cerebral ischemia in the rat hippocampus using in vivo brain microdialysis, Neurosci. Lett., 240 (1998), 53–57]. Although several methods are available for detecting NO x − levels in dialysates, these methods are either not sensitive enough or require expensive experimental equipment. The method described herein provides a convenient and sensitive procedure for determining NO x − levels in dialysates. This method is useful for the in vivo study of NO production from various brain regions in various pathological conditions, and can be applied to other tissues. Themes: Disorders of the Nervous System Topics: Ischemia

Melatonin prevents increases in neural nitric oxide and cyclic GMP production after transient brain ischemia and reperfusion in the Mongolian gerbil (Meriones unguiculatus).

While nitric oxide (NO) has been implicated as a mediator of glutamate excitotoxicity after cerebral ischemia/reperfusion, melatonin has been reported to inhibit brain NO production by suppressing nitric oxide synthase. The purpose of the present studies was to determine the effect of exogenous melatonin administration on NO-induced changes during brain ischemia/reperfusion. Indicators of cerebral cortical and cerebellar NO production [nitrite/nitrate levels and cyclic guanosine monophosphate (cGMP)] were used to estimate neural changes after transient bilateral carotid artery ligation followed by reperfusion in adult Mongolian gerbils (Meriones unguiculatus). Results show for the first time that melatonin prevents the increases in NO and cGMP production after transient ischemia/reperfusion in frontal cerebral cortex and cerebellum of Mongolian gerbils. The inhibitory effect of melatonin on NO production and its ability to scavenge free radicals and the peroxynitrite anion may be responsible for the protective effect of melatonin on neuronal structures during transient ischemia followed by reperfusion.

Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production

Cellular origins of methylarginines are not precisely known but the presence of free methyl and dimethylarginines in the brain were reported. We have investigated the circulating concentrations of asymmetrical dimethylarginine NG,NG-dimethylarginine (ADMA), NG,N′G-dimethylarginine (SDMA), nitrate and nitrite levels in drug naive first episode schizophrenic patients and matched control subjects. Three of those patients were treated with neuroleptics for 3 months. Plasma ADMA levels increased significantly but nitrate levels were significantly low compared to control subjects. Drug treatment apparently lowered ADMA levels and increased nitrate levels in plasma. Methylation of arginine to methylarginines may have an important role in regulating signal transduction through the nitric oxide system in the brain, and suggest novel therapeutic targets.

Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production

Cellular origins of methylarginines are not precisely known but the presence of free methyl and dimethylarginines in the brain were reported. We have investigated the circulating concentrations of asymmetrical dimethylarginine N G, N G-dimethylarginine (ADMA), N G, N′ G-dimethylarginine (SDMA), nitrate and nitrite levels in drug naive first episode schizophrenic patients and matched control subjects. Three of those patients were treated with neuroleptics for 3 months. Plasma ADMA levels increased significantly but nitrate levels were significantly low compared to control subjects. Drug treatment apparently lowered ADMA levels and increased nitrate levels in plasma. Methylation of arginine to methylarginines may have an important role in regulating signal transduction through the nitric oxide system in the brain, and suggest novel therapeutic targets.