Effects of S-nitrosoglutathione on acute vasoconstriction and glutamate release after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) causes acute vasoconstriction that contributes to ischemic brain injury shortly after the initial bleed. It has been theorized that decreased availability of nitric oxide (NO) may contribute to acute vasoconstriction. Therefore we examined the effect of the NO donor N-nitroso glutathione (GSNO) on acute vasoconstriction and early ischemic glutamate release after experimental SAH. METHODS: SAH was induced by the endovascular suture method in anesthetized rats. GSNO (1 micromol/L/kg, n=31) or saline (n=21) was injected 5 minutes after SAH. Sham-operated rats received GSNO (1 micromol/L/kg, n=5) 5 minutes after sham surgery. Arterial and intracranial pressures, cerebral blood flow (CBF), and extracellular glutamate release were measured serially for 60 minutes after SAH. SAH size was determined, and vascular measurements were made histologically. RESULTS: GSNO had no effect on resting blood pressure, intracranial pressure, cerebral perfusion pressure, or CBF in sham-operated animals. However, administration of GSNO after SAH was associated with significantly increased CBF (161.6+/-26.6% versus saline 37.1+/-5.5%, 60 minutes after SAH, P<0.05), increased blood vessel diameter (internal carotid artery [ICA] 285.0+/-16.5 microm versus saline 149.2+/-14.1 microm, P<0.01), decreased vessel wall thickness (ICA12.9+/-0.7 microm versus saline 25.1+/-1.6 microm, P<0.01), and decreased extracellular glutamate levels (3315.6+/-1048.3% versus saline469. 7+/-134.3%, P<0.05). Blood pressure decreased transiently, whereas intracranial pressure, cerebral perfusion pressure, and SAH size were not affected. CONCLUSIONS: These results suggest that GSNO can reverse acute vasoconstriction and prevent ischemic brain injury after SAH. This further implies that acute vasoconstriction contributes significantly to ischemic brain injury after SAH and is mediated in part by decreased availability of NO.     

大鼠脑缺血再灌流脑区一氧化氮变化的研究

目的研究大鼠脑缺血及再灌流后脑部一氧化氮的变化。方法采用荧光法和放射免疫法测定４个脑区一氧化氮（ＮＯ）代谢产物ＮＯ２和环磷酸鸟苷（ｃＧＭＰ）。结果脑缺血１０ｍｉｎ,各脑区ＮＯ２和ｃＧＭＰ含量明显增高;脑缺血３０ｍｉｎ,各脑区ＮＯ２和ｃＧＭＰ含量开始下降。缺血１０ｍｉｎ再灌流１５ｍｉｎ以及缺血３０ｍｉｎ再灌流１５ｍｉｎ,各脑区ＮＯ２和ｃＧＭＰ含量再次增加,与单纯脑缺血组相比,有显著差异性（Ｐ＜０．０５或Ｐ＜０．０１）。结论ＮＯ参与了脑缺血再灌流的损伤过程     

Relation of cerebral energy metabolism and extracellular nitrite and nitrate concentrations in patients after aneurysmal subarachnoid hemorrhage.

In a prospective clinical investigation on neurochemical intensive care monitoring, the authors' aim was to elucidate the temporal profile of nitric oxide metabolite concentrations-that is, nitrite and nitrate (NO(x))--and compounds related to energy-metabolism in the cerebral interstitium of patients after aneurysmal subarachnoid hemorrhage (SAH). During aneurysm surgery, microdialysis probes were implanted in cerebral white matter of the vascular territory most likely affected by vasospasm. Temporal profiles of NO(x) were analyzed in a subset of 10 patients (7 female, 3 male, mean age = 47 +/- 14 years). Microdialysis was performed for 152 +/- 63 hours. Extracellular metabolites (glucose, lactate, pyruvate, glutamate) were recovered from the extracellular fluid of the cerebral parenchyma. NO(x) was measured using a fluorometric assay. After early surgery, SAH patients revealed characteristic decreases of NO(x) from initial values of 46.2 +/- 34.8 micromol/L to 23.5 +/- 9.0 micromol/L on day 7 after SAH (P < 0.05). Decreases in NO(x) were seen regardless of development of delayed ischemia (DIND). Overall NO(x) correlated intraindividually with glucose, lactate, and glutamate (r = 0.58, P < 0.05; r = 0.32, P < 0.05; r = 0.28, P < 0.05; respectively). After SAH, cerebral extracellular concentrations of NO metabolites decrease over time and are associated with concomitant alterations in energy-or damage-related compounds. This could be related to reduced NO availability, potentially leading to an imbalance of vasodilatory and vasoconstrictive factors. On the basis of the current findings, however, subsequent development of DIND cannot be explained by a lack of vasodilatory NO alone.     

Age-related changes of the nitric oxide system in the rat brain

This work examines the age-related changes of the NO pathway in the central nervous system (CNS), analyzing nitric oxide synthase (NOS) isoform expression, the level of nitrotyrosine-modified proteins, and the NOS activity in the cerebral cortex, decorticated brain (basal ganglia, thalamus, hypothalamus, tegtum and tegmentum) and cerebellum of young, adult and aged rats. Our data demonstrate that the different NOS isoforms are not uniformly expressed across the CNS. In this sense, the nNOS and eNOS isoenzymes are expressed mainly in the cerebellum and decorticated brain, respectively, while the iNOS isoenzyme shows the highest level in cerebellum. Concerning age, in the cerebral cortex nNOS significantly increased its expression only in adult animals; meanwhile, in the cerebellum the eNOS expression decreased whereas iNOS increased in adult and aged rats. No age-related changes in any isoform were found in decorticated brain. NOS activity, determined by nitrate plus nitrite quantification, registered the highest levels in the cerebellum, where the significant increase detected with aging was probably related to iNOS activity. The number of nitrotyrosine-modified immunoreactive bands differed among regions; thus, the highest number was detected in the decorticated brain while the cerebellum showed the least number of bands. Finally, bulk protein nitration increased in cerebral cortex only in adult animal. No changes were found in the decorticated brain, and the decrease detected in the cerebellum of aged animals was not significant. According to these results, the NO pathway is differently modified with age in the three CNS regions analyzed.     

Changes in NOS protein expression and activity in the rat hippocampus,entorhinal and postrhinal cortices after unilateral electrolytic perirhinal cortex lesions

The integrity of the perirhinal cortex is critical for certain types of learning and memory. One important issue relating to the function of this region is its interaction with other brain areas that play a role in memory processing. This study investigates the time course of changes in activity and protein expression of nitric oxide synthase (NOS), which transforms L-arginine into nitric oxide (NO) and citrulline, in the hippocampus and the entorhinal and postrhinal cortices after unilateral electrolytic lesions of the perirhinal cortex. Electrolytic lesions of the perirhinal cortex resulted in long lasting changes in NOS activity and protein expression in the entorhinal and postrhinal cortices (< or = 2 weeks post-lesion). In contrast, there was a small and transient decrease in nNOS expression (with no change in NOS activity) in the dorsal portion of the hippocampus. iNOS was not expressed in any region examined at any time point. These findings provide the first evidence that electrolytic lesions of the perirhinal cortex can result in long-term neurochemical changes in its anatomically related structures. Given that NO has been implicated in neuroplasticity processes, the interpretation of memory impairments induced by electrolytic lesions of the perirhinal cortex (and possibly, therefore, other brain regions) need to be considered with regard to these findings.     

Effects of chronic nicotine administration on nitric oxide synthase expression and activity in rat brain

Although there is substantial evidence concerning the influence of nicotine on nitric oxide (NO) synthesis in the vascular system, there are fewer studies concerning the central nervous system. Although NO metabolites (nitrates/nitrites) increase in several rat brain regions after chronic injection of nicotine, the cellular origin of this rise in NO levels is not known. The aim of the present work was to assess the effects of repetitive nicotine administration on nitric oxide synthase (NOS) expression and activity in male and female rat brains. To determine levels of nitrate/nitrite, the Griess reaction was carried out in tissue micropunched from the frontal cortex, striatum, and accumbens of both male and female rats untreated (naïve) or injected with saline or nicotine (0.4 mg/kg for 15 days). In parallel, coronal sections of fixed brains from equally treated animals were immunostained for neuronal NOS or histochemically labelled for NADPH‐diaphorase activity. Nicotine treatment increased NO metabolites significantly in all brain regions compared with naïve or saline‐treated rats. By contrast, analysis of the planimetric counting of NOS/NADPH‐diaphorase‐positive neurons failed to demonstrate any significant effect of the nicotine treatment. A significant decrease was observed with both techniques employed in saline‐injected female rats compared with naïve animals, suggesting a stress response. The mismatch between the biochemical and the histological data after chronic nicotine treatment is discussed. The up‐regulation of NO sources other than neurons is proposed. © 2002 Wiley‐Liss, Inc.     

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.     

Nitric oxide levels in rat cortex,hippocampus, cerebellum,and brainstem after impact acceleration head injury

Nitric oxide (NO) is a potential mediator of secondary brain injury in the settings of cerebral ischemia and inflammation. Traumatic brain injury (TBI) alters the levels of stable end products of NO metabolism. We investigated these changes and attempted to identify brain regions that were unique with regard to NO production in the period immediately after TBI. The experiment involved assaying nitrite-nitrate concentrations in the rat cortex, cerebellum, hippocampus, and brainstem after impact-acceleration head injury. Five rats comprised the sham-operated (control) group, five sustained mild head injury (MHI), and five sustained severe head injury (SHI). There was a uniform decline in the tissue concentrations of NO metabolites in all four brain regions in both injured groups. There were no significant differences in the concentrations of NO metabolites among the various sites tested in the MHI group; however, there appeared to be a relationship between degree of decline in NO levels and amount of trauma sustained by a given region in the SHI group. In these rats, NO dropped to the lowest levels in the brain region where the direct trauma was most severe. The results suggest that nitrite-nitrate levels in these four brain regions fall below normal in the first 5 min after impact trauma. This decrease may, in part, be related to reduced activity of all nitric oxide synthase isoforms, which would cause a drop in the levels of NO metabolites. We believe that this decline may be linked to, and may even cause, the global decrease in cerebral blood flow that occurs in the initial stages of TBI.     

Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats.

The objective of the present study was to investigate the possible neuroprotective effect of resveratrol against streptozotocin-induced hyperglycaemia in the rat brain and medulla spinalis. Thirty adult male Wistar rats were divided into three groups as follows: control group, streptozotocin-induced diabetic-untreated group, and streptozotocin-induced diabetic resveratrol-treated group. Diabetes was induced by a single injection of streptozotocin (STZ) (60 mg/kg body weight). Three days after streptozotocin injection, resveratrol (10 mg/kg) was injected intraperiteonally daily over 6 weeks to the rats in the treatment group. Six weeks later, seven rats from each group were killed and the brain stem and cervical spinal cord were removed. The hippocampus, cortex, cerebellum, brain stem and spinal cord were dissected for biochemical studies (lipid peroxidation measuring malondialdehyde [MDA], xanthine oxidase [XO], nitric oxide [NO] and glutathione). MDA, XO and NO levels in hippocampus, cortex, cerebellum, brain stem and spinal cord in the streptozotocin-induced diabetic-untreated group increased significantly. Treatment with resveratrol significantly reduced MDA, XO and NO production and increased glutathione levels when compared to the streptozotocin-induced diabetic-untreated group. This study demonstrates that resveratrol is a potent neuroprotective agent against diabetic oxidative damage.     

The stress effects of a single injection of isotonic saline solution: systemic (blood) and central (frontal cortex and dorsal and ventral hippocampus)

In experiments with animals, a group that is injected with the vehicle in which a drug of interest is dißsolved is often used as a control. However, even a single injection of a vehicle is a stressor, i.e., “treatment stress,” which may significantly affect some stress-sensitive indices. In the present study, we report some data on the effects of a single intraperitoneal injection of isotonic saline solution on the contents of corticosterone, nitric oxide metabolites, and oxidative capacity, as well as on the expression of proteins and mRNAs of proinflammatory cytokines in the blood and brain regions of rats within one day after the injection as compared to intact animals. At the early time points after the injection, corticosterone contents were substantially elevated in the blood and ventral hippocampus. The content of nitric oxide metabolites decreased in the blood and remained stably low within 2–24 h after the injection. The injection did not affect the contents of proinflammatory cytokines in the blood; however, early after the injection the expression of IL-1ß mRNA decreased in the ventral hippocampus and frontal cortex, whereas 24 h after this treatment, the expression of TNF-a mRNA increased by a factor of 4 in the frontal cortex. Thus, a single injection of isotonic saline solution had a clear stress-producing effect, which was observed at the systemic level and in stress-sensitive brain regions. The strength of this stressful event was sufficient to activate the hypothalamus–pituitary–adrenal axis but not sufficient to induce a significant inflammatory response. The frontal cortex was most sensitive to this treatment; the alterations in the ventral hippocampus were less expressed, whereas the dorsal hippocampus was most stress resistant. Our data show that it is important to consider and thoroughly analyze the effects of “treatment stress” in experiments using injections of biologically active substances.     

自发性高血压大鼠脑缺血后脑区一氧化氮的变化

目的：研究自发性高血压大鼠（SHR）脑缺血后大脑皮质、海马、纹状体和小脑组织中一氧化氮（NO）的变化。采用放射免疫法和荧光分光光度法检测脑组织中一氧化氮合酶（NOS）和亚硝酸盐（NO2）的含量。结果显示SHR脑缺血10min,各脑区NOS和NO2,的含量均明显高于假手术组（P<0．01或P＜005）。说明了SHR脑缺血早期脑组织NO的生成增加．提示用特异的NO生成抑制剂类药物,可能有助于脑缺血的治疗。     

大鼠蛛网膜下腔出血血清、脑组织一氧化氮变化与脑缺血损害

目的:探讨一氧化氮(NO)在蛛网膜下腔出血(SAH)缺血性脑损害中作用。方法:应用非开颅大鼠模型,观察24h内脑微区血流量(CBF)和颅内血清及脑组织NO水平动态改变,3d后对海马CA1区行病理检查。结果:SAH后CBF和血清NO降低,脑组织NO增加,海马CA1区神经元明显受损。结论:血清NO减少、脑组织NO增加与SAH脑缺血损害的发生,发展有密切关系。     

Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum

The biological roles of nitric oxide (NO) and cGMP as inter- and intracellular messengers have been intensively investigated during the last decade. NO and cGMP both mediate physiological effects in the cardiovascular, endocrinological, and immunological systems as well as in central nervous system (CNS). In the CNS, activation of theN-methyl-d-aspartic acid (NMDA) type of glutamatergic receptor induces Ca²⁺-dependent NOS and NO release, which then activates soluble guanylate cyclase for the synthesis of cGMP. Both compounds appear to be important mediators in long-term potentiation and long-term depression, and thus may play important roles in the mechanisms of learning and memory. Aging and the accumulation of amyloid β (Aβ) peptides are important risk factors for the impairment of memory and development of dementia. In these studies, the mechanism of basal- and NMDA receptor-mediated cGMP formation in different parts of adult and aged brains was evaluated. The relative activity of the NO cascade was determined by assay of NOS and guanylate cyclase activities. In addition, the effect of the neurotoxic fragment 25–35 of Aβ (Aβ) peptide on basal and NMDA receptor-mediated NOS activity was investigated. The studies were carried out using slices of hippocampus, brain cortex, and cerebellum from 3- and 28-mo-old rats. Aging coincided with a decrease in the basal level of cGMP as a consequence of a more active degradation of cGMP by a phosphodiesterase in the aged brain as compared to the adult brain. Moreover, a loss of the NMDA receptor-stimulated enhancement of the cGMP level determined in the presence of cGMP-phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was observed in hippocampus and cerebellum of aged rats. However, this NMDA receptor response was preserved in aged brain cerebral cortex. A significant enhancement of the basal activity of NOS by about 175 and 160% in hippocampus and cerebellum, respectively, of aged brain may be involved in the alteration of the NMDA receptor response. The neurotoxic fragment of Aβ, peptide 25–35, decreased significantly the NMDA receptor-mediated calcium, and calmodulin-dependent NO synthesis that may then be responsible for disturbances of the NO and cGMP signaling pathway. We concluded that cGMP-dependent signal transduction in hippocampus and cerebellum may become insufficient in senescent brain and may have functional consequences in disturbances of learning and memory processes. Aβ peptide accumulated during brain aging and in Alzheimer disease may be an important factor in decreasing the NO-dependent signal transduction mediated by NMDA receptors.     

Age-dependent vulnerability of brain choline acetyltransferase activity to transient cerebral ischemia in rats

Male Fischer-344 rats aged 6, 12, or 24 months were subjected to four-vessel occlusion cerebral ischemia to assess age-dependent ischemic vulnerability of cholinergic and GABAergic neurons based on choline acetyltransferase (EC 2.3.1.6) and glutamic acid decarboxylase (EC 4.1.1.15) activities. Activities of both enzymes were similar (p greater than 0.05) in 6- (n = 5) and 12- (n = 5) month-old rats. Mean +/- SEM choline acetyltransferase activities in the cortex, hippocampus, striatum, and cerebellum of 6-month-old controls were 75 +/- 5, 123 +/- 9, 415 +/- 9, and 50 +/- 4 nmol acetylcholine/hr/mg protein, respectively, and were 20-30% lower (p less than 0.05) in all brain regions except the cerebellum in 24-month-old controls. Choline acetyltransferase activity was unaffected by ischemia in 6- and 12-month-old rats but was reduced by 30-60% in 24-month-old rats. Mean +/- SEM glutamic acid decarboxylase activities in the cortex, hippocampus, striatum, and cerebellum of 6-month-old controls were 98 +/- 8, 86 +/- 7, 144 +/- 13, and 125 +/- 9 nmol gamma-aminobutyric acid/hr/mg protein, respectively, and 25-35% lower in all regions of 24-month-old controls. After 30 minutes of ischemia and 5 days of recovery, glutamic acid decarboxylase activities were reduced (p less than 0.05) in all brain regions and age groups. However, its activity was decreased (p less than 0.05 compared with age-matched controls) by 55% in the cortex and 79% in the hippocampus of 24-month-old rats compared with 30% and 45% in younger rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuronal nitric oxide synthase (NOS-I) knockout increases the survival rate of neural cells in the hippocampus independently of BDNF

Investigations regarding the regulation of adult neurogenesis, i.e., the generation of new neurons from progenitor cells, have revealed a high degree of complexity. Although the pleiotropic messenger molecule nitric oxide (NO) has been suggested to modulate adult neurogenesis, the evidence is inconclusive due to the presence of different NO synthase isoforms in the brain. We therefore investigated whether stem cell proliferation or survival is altered in mice lacking neuronal nitric oxide synthase (NOS-I) or both endothelial and neuronal NOS (NOS-I/-III double knockout). While proliferation of neural stem cells was only numerically, but not significantly increased in NOS-I knockdown animals, the survival of newly formed neurons was substantially higher in NOS-I-deficient mice. In contrast, NOS-I/-III double knockout had significantly decreased survival rates. QRT-PCR in NOS-I-deficient mice revealed neither NOS-III upregulation compensating for the loss of NOS-I, nor alterations in VEGF levels as found in NOS-III-deficient animals. As changes in BDNF expression or protein levels were observed in the cortex, cerebellum and striatum, but not the hippocampus, the increase in stem cell survival appears not to be due to a BDNF mediated mechanism. Finally, NOS-I containing neurons in the dentate gyrus are rare and not localized close to progenitor cells, rendering direct NO effects on these cells unlikely. In conclusion, we suggest that NO predominantly inhibits the survival of new-born cells, by an indirect mechanism not involving BDNF or VEGF. Together, these results emphasize the important role of the different NOS isoforms with respect to adult neurogenesis.     

A pharmacokinetic study of clomipramine in regions of the brain

The pharmacokinetic profiles of clomipramine (CMP) and the serial changes of its concentration in specific brain regions were investigated in rats after an acute treatment with intravenous CMP (10 mg/kg). The CMP concentrations in plasma declined triexponentially and fitted a three-compartment open model. The brain to plasma concentration ratio showed a constant value, 22.2 +/- 4.9, 30 minutes after the injection. Regional brain differences in the CMP distribution and accumulation were also found. Four hours after the injections, the hippocampus was found to have the highest drug concentration, and the concentrations in this region were in the following order; thalamus, striatum, amygdala, cortex greater than pons + medulla oblongata greater than hypothalamus, bulbus olfactorius + septum, mesencephalon greater than cerebellum. Particularly, unique kinetics were observed in the cortex, amygdala and hippocampus.     

Lactate and free fatty acids after subarachnoid hemorrhage

The hypothesis that lactate and free fatty acids (FFA) are elevated in the first minutes after subarachnoid hemorrhage (SAH) is tested. Adult rats were subjected to an endovascular SAH through the right internal carotid artery while under anesthesia. The brains were frozen in-situ at 15, 30, 60 min, and 24 h post-hemorrhage. Regional measures of tissue lactic acid and FFA were made in the hippocampi, ipsilateral cortex, contralateral cortex, and cerebellum. Lactic acid levels were significantly elevated from sham animals in each region within the first hour (p<0.0001 cerebellum, right, and contralateral cortex, p<0.01 hippocampus), but did not change significantly over the first hour. At 24 h post-hemorrhage, there was no significant difference in the lactic acid levels from controls. Similarly, total FFA were significantly higher in each region as compared to sham operated controls within the first hour (p<0.001 cerebellum, p<0.05 hippocampus, p<0.05 contralateral cortex, p<0.0001 ipsilateral cortex). By 24 h, there was no significant difference in FFA levels from shams. The data indicate that aerobic metabolism fails and cellular damage with degradation of cell membranes occurs in the first minutes after SAH, and lasts for at least 1 h. However, this process is stabilized within 24 h in our model. Although the largest effect was seen in the ipsilateral cortex, all areas of the brain were effected.     

Role of Nitric Oxide in the Epileptogenesis of EL Mice

Summary: Purpose : To understand the role of nitric oxide (NO) in the regulation of seizures, we measured the extracellular levels of the NO metabolites nitrite and nitrate as indices of NO generation in the parietal cortex, hippocampus, and temporal cortex of EL mice. Furthermore, alterations of neuronal, endothelial, and inducible nitric oxide synthetase (nNOS, eNOS, and iNOS, respectively) were observed to correlate them with epileptogenesis.
Methods : EL mice of 20 weeks and 30 weeks of age (before and after the establishment of epileptogenesis, respectively) were used. Nitrite was quantified using the specific absorbancy of diazo dye. NOS isoenzymes (nNOS, iNOS, and eNOS) were also investigated in the hippocampus during development until mice were 30 weeks old. Samples (total protein, 8·33 to 8·43 μg) were separated by sodium dodecyl sulfate—polyacrylamide gel electrophoresis and identified by immunoblotting.
Results : EL mice that experienced repetitive seizures showed a remarkable increase in nitrite in the hippocampus at 30 weeks of age compared with EL mice that had no experience of seizures. nNOS and iNOS were major and minor components, respectively, and both increased in parallel with the development of epileptogenesis. eNOS was not detectable.
Conclusions : Excess iNOS (and subsequent increase in harmful NO) and deficient eNOS (and subsequent decrease in NO identified as an endothelium-derived relaxing factor) may work together to form a focus complex.     

Effects of deltamethrin on nitric oxide synthase and poly(ADP-ribose) polymerase in rat brain

The effects of deltamethrin on the activities of nitric oxide synthase (NOS) and poly(ADP-ribose) polymerase (PARP) and the protein expression of neuronal NOS (nNOS) and PARP in rat brain were investigated in the present study. The activity of NOS was significantly increased in cortex and hippocampus at 5 h after deltamethrin treatment, and maintained at an increased level at 24 h. The activity of PARP was also elevated at the same time points in the same brain regions of treated rats. By immunohistochemical analysis, it was demonstrated that the nNOS-immunoreactive cells were markedly increased at 24 h after treatment in the cortex and hippocampus, whereas few nNOS-immunoreactive cells were observed in the same brain regions of control and treated rats at 5 h after treatment. The immunoreactivity for PARP was also increased in the same brain regions, showing the similar time course of the induction of nNOS by deltamethrin. These results indicate that deltamethrin increases the activities of NOS and PARP and initiates the protein expression of nNOS and PARP, suggesting that NOS and PARP might play important roles in neurotoxicity of deltamethrin.