Nitric oxide, mitochondria and neurological disease

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis. There is also a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in these disorders. It is now well documented that NO and its toxic metabolite, peroxynitrite (ONOO-), can inhibit components of the mitochondrial respiratory chain leading, if damage is severe enough, to a cellular energy deficiency state. Within the brain, the susceptibility of different brain cell types to NO and ONOO- exposure may be dependent on factors such as the intracellular reduced glutathione (GSH) concentration and an ability to increase glycolytic flux in the face of mitochondrial damage. Thus neurones, in contrast to astrocytes, appear particularly vulnerable to the action of these molecules. Following cytokine exposure, astrocytes can increase NO generation, due to de novo synthesis of the inducible form of nitric oxide synthase (NOS). Whilst the NO/ONOO- so formed may not affect astrocyte survival, these molecules may diffuse out to cause mitochondrial damage, and possibly cell death, to other cells, such as neurones, in close proximity. Evidence is now available to support this scenario for neurological disorders, such as multiple sclerosis. In other conditions, such as ischaemia, increased availability of glutamate may lead to an activation of a calcium-dependent nitric oxide synthase associated with neurones. Such increased/inappropriate NO formation may contribute to energy depletion and neuronal cell death. The evidence available for NO/ONOO--mediated mitochondrial damage in various neurological disorders is considered and potential therapeutic strategies are proposed.     

Nitric oxide

Nitric oxide (NO)--a 1:1 combination of the two most abundant gaseous elements--is a biological mediator of complexity, subtlety and protean effects. The history of its discovery as a mediator is fascinating, and its role in mammalian biology and medicine is proving to be of fundamental importance.     

Nitric oxide donors

Nitric oxide (NO) donors are pharmacologically active substances that release NO in vivo or in vitro. NO has a variety of functions such as the release of prostanoids, inhibition of platelet aggregation, effect on angiogenesis, and production of oxygen free radicals. This report discusses the chemical and pharmacological characteristics of NO donors, their effect on platelet function and cyclooxygenase, their cardiac action including myocardial infarction, and release of superoxide anions. This review stresses NO tolerance and the effect of NO donors on angiogenesis in myocardial infarction and in solid tumors.     

肠道菌群与神经系统疾病

人类肠道菌群是数以万亿的细菌组成的高度多样化的生态系统,菌群失调与多个系统疾病有关联。肠道菌群通过菌群-肠-脑轴与神经系统多途径双向互作,能引起神经免疫炎症反应、肠黏膜和血脑屏障功能改变、直接刺激迷走神经和肠道神经系统脊神经、神经内分泌-下丘脑-垂体-肾上腺轴,造成神经系统疾病。肠道菌群的代谢产物也有一定的作用。文中综述自闭症谱系障碍、多发性硬化、帕金森病、癫痫、吉兰巴雷综合征、阿尔茨海默病、视神经脊髓炎、肝性脑病、肌萎缩侧索硬化、精神分裂症、抑郁症、慢性疲劳综合征、亨廷顿病、脑卒中等肠道菌群改变特征及其干预措施的研究进展。目前肠道菌群的研究还处在初级阶段,因果关系和机制方面的研究比较少,这对精准实施菌群临床干预措施具有重要意义,期待将来有所突破成为一些神经系统疾病治疗的新路径。     

Nitric oxide evolution and perception

Various experimental data indicate signalling roles for nitric oxide (NO) in processes such as xylogenesis, programmed cell death, pathogen defence, flowering, stomatal closure, and gravitropism. However, it still remains unclear how NO is synthesized. Nitric oxide synthase-like activity has been measured in various plant extracts, NO can be generated from nitrite via nitrate reductase and other mechanisms of NO generation are also likely to exist. NO removal mechanisms, for example, by reaction with haemoglobins, have also been identified. NO is a gas emitted by plants, with the rate of evolution increasing under conditions such as pathogen challenge or hypoxia. However, exactly how NO evolution relates to its bioactivity in planta remains to be established. NO has both aqueous and lipid solubility, but is relatively reactive and easily oxidized to other nitrogen oxides. It reacts with superoxide to form peroxynitrite, with other cellular components such as transition metals and haem-containing proteins and with thiol groups to form S-nitrosothiols. Thus, diffusion of NO within the plant may be relatively restricted and there might exist 'NO hot-spots' depending on the sites of NO generation and the local biochemical micro-environment. Alternatively, it is possible that NO is transported as chemical precursors such as nitrite or as nitrosothiols that might function as NO reservoirs. Cellular perception of NO may occur through its reaction with biologically active molecules that could function as 'NO-sensors'. These might include either haem-containing proteins such as guanylyl cyclase which generates the second messenger cGMP or other proteins containing exposed reactive thiol groups. Protein S-nitrosylation alters protein conformation, is reversible and thus, is likely to be of biological significance.     

Nitric oxide and neurons.

In the past 2 years powerful evidence has emerged to suggest that nitric oxide functions as a neurotransmitter in both the central and peripheral nervous systems. Recent evidence suggests that it may play a role in mediating forms of synaptic plasticity such as long-term potentiation in the CA1 region of the hippocampus, and long-term depression in the cerebellum. Abnormal secretion of nitric oxide may be responsible for the neurotoxicity mediated by NMDA receptors that results in the pathophysiology of strokes and neurodegenerative diseases.     

Nitric oxide and endothelial permeability

Hinder, Frank, Michael Booke, Lillian D. Traber, and DanielL. Traber. Nitric oxide and endothelial permeability.J. Appl. Physiol. 83(6):1941-1946, 1997.Nitric oxide synthase inhibition reversessystemic vasodilation during sepsis but may increase endothelialpermeability. To assess adverse effects on the pulmonary vasculature,12 sheep were chronically instrumented with lung lymph fistulas andhydraulic pulmonary venous occluders. Escherichia coli endotoxin (lipopolysaccharide; 10 ng · kg¹ · min¹)was continuously infused for 32 h. After 24 h, six animals received 25 mg/kg of N-nitro-L-argininemethyl ester (L-NAME), and sixreceived saline. All sheep developed a hyperdynamic circulatoryresponse and elevated lymph flows by 24 h of lipopolysaccharideinfusion. L-NAME reversed systemic vasodilation, increased pre- and postcapillary pulmonary vascular resistance index, pulmonary arterial pressure, and,transiently, effective pulmonary capillary pressure. Lung lymph flowswere not different between groups at 24 h or thereafter. Calculated aschanges from baseline, however, lung lymph flow was higher in theL-NAME group than in the controlanimals, with a trend toward lower lymph-to-plasma proteinconcentration ratio at 25 h. Permeability analysis at 32 h by thevenous occlusion technique showed normal reflection coefficients andelevated filtration coefficients without differences between groups.Reversal by L-NAME of thesystemic vasodilation during endotoxemia was associated with highpulmonary vascular resistance without evidence of impaired pulmonaryendothelial barrier function.

     

Nitric oxide and immune response

Nitric oxide (NO), initially described as a physiological mediator of endothelial cell relaxation plays an important role in hypotension. It is an intercellular messenger and has been recognized as one of the most versatile players in the immune system. Cells of the innate immune system--macrophages, neutrophils and natural killer (NK) cells use pattern recognition receptors to recognize molecular patterns associated with pathogens. Activated macrophages then inhibit pathogen replication by releasing a variety of effector molecules, including NO. In addition to macrophages, a large number of other immune system cells produce and respond to NO. Thus, NO is important as a toxic defense molecule against infectious organisms. It also regulates the functional activity, growth and death of many immune and inflammatory cell types including macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils and NK cells. However, the role of NO in non-specific and specific immunity in vivo and in immunologically mediated diseases and inflammation is poorly understood. This review discusses the role of NO in immune response and inflammation and its mechanisms of action in these processes.     

学术思想才是第一位的——一氧化氮发现的故事及启示

１９８０年美国药理学家Ｆｕｒｃｈｇｏｔ以其精妙的实验在Ｎａｔｕｒｅ上发表论文,指出乙酰胆碱（ＡＣｈ）的舒血管作用依赖血管内皮释放的某种可扩散物质［１］。随后他们又发现缓激肽（ＢＫ）等多种扩血管物质的作用也是通过类似的机理,并将该物质命名为（血管）内皮...     

Nitric oxide and Drosophila development

Mechanisms controlling the transition of precursor cells from proliferation to differentiation during organism development determine the distinct anatomical features of tissues and organs. NO may mediate such a transition since it can suppress DNA synthesis and cell proliferation. Inhibition of NOS activity in the imaginal discs of Drosophila larvae results in hypertrophy of tissues and organs of the adult fly, whereas ectopic overexpression of NOS has the reciprocal, hypotrophic, effect. Furthermore, NO production is crucial for the establishment of ordered neuronal connections in the visual system of the fly, indicating that NO affects the acquisition of the differentiated phenotype by the neural tissue. Increasing evidence points to a broad role that NO may play in animal development by acting as an essential negative regulator of precursor cell proliferation during tissue and organ morphogenesis.     

Nitric oxide and atherosclerosis.

Endothelial dysfunction has been shown in a wide range of vascular disorders including atherosclerosis and related diseases. Here, we examine and address the complex relationship among nitric oxide (NO)-mediated pathways and atherogenesis. In view of the numerous pathophysiological actions of NO, abnormalities could potentially occur at many sites: (a) impairment of membrane receptors in the arterial wall that interact with agonists or physiological stimuli capable of generating NO; (b) reduced concentrations or impaired utilization of l-arginine; (c) reduction in concentration or activity both of inducible and endothelial NO synthase; (d) impaired release of NO from the atherosclerotic damaged endothelium; (e) impaired NO diffusion from endothelium to vascular smooth muscle cells followed by decreased sensitivity to its vasodilator action; (f) local enhanced degradation of NO by increased generation of free radicals and/or oxidation-sensitive mechanisms; and (g) impaired interaction of NO with guanylate cyclase and consequent limitation of cyclic GMP production. Therefore, one target for new drugs should be the preservation or restoration of NO-mediated signaling pathways in arteries. Such novel therapeutic strategies may include administration of l-arginine/antioxidants and gene-transfer approaches.     

Nitric oxide and anti-protozoan chemotherapy

Constitutive nitric oxide (NO) is generated by constitutively expressed types of NO-synthase enzymes (NOS-I and -III), being involved in physiological processes such as nervous transmission and vasodilatation. Inducible NO, synthesized by the NO-synthase isoform NOS-II, is an anti-pathogen and tumoricidal agent. However, inducible NO production requires a tight control because of cytotoxic and immune-modulation activity. NO produced by human and canine macrophages has long been demonstrated to be involved in the intracellular killing of Leishmania. Mechanisms of parasite survival and persistence in the host have been throughly investigated, and include suppression of NOS-II and the parasite entry into NOS-II negative cells. Both intracellular and extracellular morphotypes of Trypanosoma cruzi are killed by NO in vitro and in vivo, although a role of NO in the pathogenesis of heart disease has been reported. Killing of extracellular protozoa such as Trichomonas vaginalis and Naegleria fowleri by activated macrophages is also mediated by NO. The main control of Plasmodium spp infection in human and murine hepatocytes, and in human monocytes is achieved by NO-mediated mechanisms. Protection from severe malaria in African children has been found associated with polymorphisms of the NOS-II promoter; however, a pathogenic role of endogenous NO has been documented in cerebral malaria. Although several macromolecules are putative NO targets, recent experimental work has shown that NO-releasing compounds inhibit cysteine proteases (CP) of P. falciparum, T. cruzi and L. infantum in a dose-dependent manner. CPs are present in a wide range of parasitic protozoa and appear to be relevant in several aspects of the life cycle and of the parasite-host relationships. Comparative analysis of 3-D amino acid sequence models of CPs from a broad range of living organisms, from viruses to mammals, suggests that the Sy atom of the Cys catalytic residue undergoes NO-dependent chemical modification (S-nytrosilation and disulfide bridge formation), with the concomitant loss of enzyme activity. The NO-donor S-nitroso-N-acetilpenicillamine (SNAP) was shown to kill T. cruzi epimastigotes and L. infantum promastigotes in culture, while a combination of nitrite plus acid organic salts was highly effective against L. major amastigotes in mouse macrophages. A parasitostatic effect--with both encystation and excystation inhibition--of S-nitrosoglutathione and spermine-NONOate was documented in trophozoite cultures of Giardia duodenalis. Recently, a novel formulation of metronidazole bearing a NO-releasing group was found to enhance significantly the in vitro killing of Entamoeba histolytica trophozoites, compared to metronidazole. So far, only two clinical studies were performed on human patients, suffering from cutaneous leishmaniasis. In one study, 16 Ecuadorean patients were treated with a SNAP cream administered on lesions for 10 days. All lesions were parasitologically cured and clinically healed by day 30. In the second study, a different NO-producing cream (basically nitrite in acidic environment) was employed to treat 40 Syrian patients. Only 28% of them showed improvement and 12% were cured by day 60. In conclusion, despite the wide evidence that NO can be regarded as a natural anti-protozoal weapon, little efforts have been made to develop and test NO-based drugs in human medicine. This is mainly due to the difficulty in designing suitable chemical carriers able to release the right amount of NO, in the right place and in the right time, to avoid toxic effects against non-target host cells.     

Nitric oxide insufficiency and atherothrombosis

Nitric oxide (NO) is a structurally simple compound that participates in a wide range of biological reactions to maintain normal endothelial function and an antithrombotic intravascular milieu. Among its principal effects are the regulation of vascular tone, vascular smooth muscle cell proliferation, endothelial–leukocyte interactions, and the antiplatelet effects of the endothelium. Impaired NO bioavailability represents the central feature of endothelial dysfunction, the earliest stage in the atherosclerotic process, and also contributes to the pathogenesis of acute vascular syndromes by predisposing to intravascular thrombosis. The causes of NO insufficiency can be grouped into two fundamental mechanisms: inadequate synthesis and increased inactivation of NO. Polymorphisms in the endothelial NO synthase gene and decreased substrate or cofactor availability for this enzyme are the main mechanisms that compromise the synthesis of NO. Inactivation of NO occurs mainly through its interaction with reactive oxygen species and can be favored by a deficiency of antioxidant enzymes such as glutathione peroxidase. In this review, we present an overview of NO synthesis and biological chemistry, discuss the mechanisms of action of NO in regulating endothelial and platelet function, and explore the causes of NO insufficiency, as well as the evidence linking these causes to the pathophysiology of endothelial dysfunction and atherothrombosis.     

Nitric oxide and neuronal death

NO and its derivatives can have multiple effects, which impact on neuronal death in different ways. High levels of NO induces energy depletion-induced necrosis, due to: (i) rapid inhibition of mitochondrial respiration, (ii) slow inhibition of glycolysis, (iii) induction of mitochondrial permeability transition, and/or (iv) activation of poly-ADP-ribose polymerase. Alternatively, if energy levels are maintained, NO can induce apoptosis, via oxidant activation of: p53, p38 MAPK pathway or endoplasmic reticulum stress. Low levels of NO can block cell death via cGMP-mediated: vasodilation, Akt activation or block of mitochondrial permeability transition. High NO may protect by killing pathogens, activating NF-κB or S-nitro(sy)lation of caspases and the NMDA receptor. GAPDH, Drp1, mitochondrial complex I, matrix metalloprotease-9, Parkin, XIAP and protein-disulphide isomerase can also be S-nitro(sy)lated, but the contribution of these reactions to neurodegeneration remains unclear. Neurons are sensitive to NO-induced excitotoxicity because NO rapidly induces both depolarization and glutamate release, which together activate the NMDA receptor. nNOS activation (as a result of NMDA receptor activation) may contribute to excitotoxicity, probably via peroxynitrite activation of poly-ADP-ribose polymerase and/or mitochondrial permeability transition. iNOS is induced in glia by inflammation, and may protect; however, if there is also hypoxia or the NADPH oxidase is active, it can induce neuronal death. Microglial phagocytosis may contribute actively to neuronal loss.