Nitric oxide and sleep

Sleep Medicine Reviews (2005) 9, 101–113

www.elsevier.com/locate/smrv

PHYSIOLOGICAL REVIEW

Nitric oxide and sleep ´, Damien Colas, Pierre Parmantier, Sabine Gautier-Sauvigne Pierre Clement, Abdallah Gharib, Nicole Sarda, Raymond Cespuglio* Claude Bernard University Lyon1, INSERM U 480, EA 3734 and IFR 19, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France KEYWORDS Nitric oxide; NO synthase; Slow-wave sleep; REM sleep; Paradoxical sleep; Waking

Summary Nitric oxide (NO) is a biological messenger synthesized by three main isoforms of NO synthase (NOS): neuronal (nNOS, constitutive calcium dependent), endothelial (eNOS, constitutive, calcium dependent) and inducible (iNOS, calcium independent). NOS is distributed in the brain either in circumscribed neuronal sets or in sparse interneurons. Within the laterodorsal tegmentum (LDT), pedunculopontine tegmentum and dorsal raphe nucleus, NOS-containing neurons overlap neurons grouped according to their contribution to sleep mechanisms. The main target for NO is the soluble guanylate cyclase that triggers an overproduction of cyclic guanosine monophosphate. NO in neurons of the pontine tegmentum facilitates sleep (particularly rapid-eye-movement sleep), and NO contained within the LDT intervenes in modulating the discharge of the neurons through an auto-inhibitory process involving the co-synthesized neurotransmitters. Moreover, NO synthesized within cholinergic neurons of the basal forebrain, while under control of the LDT, may modulate the spectral components of the EEG instead of the amounts of different sleep states. Finally, impairment of NO production (e.g. neurodegeneration, iNOS induction) has identifiable effects, including ageing, neuropathologies and parasitaemia. q 2004 Published by Elsevier Ltd.

Introduction The discovery of endothelium-derived relaxing factor in the late 1980s1 initiated studies that ultimately led to the discovery of the biological paracrine messenger identified as nitric oxide (NO).2

* Corresponding author. Tel.: C33-78-77-71-26; fax: C33-7877-71-72. E-mail addresses: [email protected] (S. Gautier-Sauvigne ´), [email protected] (D. Colas), parmantier@ sommeil.univ-lyon1.fr (P. Parmantier), clement@sommeil. univ-lyon1.fr (P. Clement), [email protected] (A. Gharib), [email protected] (N. Sarda), cespugli@ sommeil.univ-lyon1.fr (R. Cespuglio). 1087-0792/$ - see front matter q 2004 Published by Elsevier Ltd. doi:10.1016/j.smrv.2004.07.004

Although this messenger is now recognized as regulating transmission and metabolism in various cells and tissues, it might also be a potent cytotoxic agent when synthesized in excess. NO is present in periphery and in the central nervous system and regulates a great variety of physiological functions including memory processes, the sleep–wake cycle, synaptic plasticity, blood flow and gastrointestinal motility.3 NO also exerts detrimental effects: its involvement in acute inflammatory processes,4 ageing and associated neurodegenerative pathologies5,6 is now recognized. The present review first recalls the essential data related to the regulatory processes associated with NO synthesis, brain anatomical distribution of NO

102 synthases (NOSs), and brain targets for NO, and then focuses on the relationships between NO and sleep in physiological and pathophysiological conditions.

NO synthesis NO is a labile gas synthesized in mammalian cells from L-arginine through enzymatic reactions catalyzed by a family of NOSs. This family currently includes three NOS isoforms identified as neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) by reference to the tissue from which they were originally purified. The above isoforms are much more widely distributed in mammalian tissues than originally suspected.7 Moreover, a widespread nomenclature based on the earliest observations classifies the nNOS and eNOS as constitutive isoforms, whereas an induction-step is assigned for iNOS expression. This nomenclature remains questionable since under physiological conditions iNOS may function as a constitutive isoform in some cells, while the genes coding for nNOS or eNOS may also be expressed under physiological conditions.8 All the NOS isoforms are homodimeric proteins in their active forms. Each monomer consists of four discrete domains (reductase, calmodulin binding, oxygenase and an N-terminal sequence specific to the isoform). Following binding with calmodulin, the NOS catalytic processes require two co-substrates (the reduced form of nicotinamide adenine dinucleotide phosphate, and oxygen) and four enzyme-bound co-factors (flavin adenine dinucleotide, flavin mononucleotide, thiolate-bound haem and tetrahydrobiopterin).7,9–12 In addition, while calcium is needed for nNOS and eNOS activities, its presence is not essential for that of iNOS since calmodulin spontaneously binds sufficiently tightly to it.11 In aerobic conditions, the NOSs catalyze the oxidation of L-arginine in two steps, the end products being L-citrulline and NO (Fig. 1).

S. Gautier-Sauvigne ´ et al.

NOS regulation NO cannot be stored in specialized vesicles owing to its strong reactivity in vivo (a half-life of a few seconds), and hence regulating its level of production lies in the control of biogenesis.13 Consequently, the regulatory mechanisms attached to NOS expression and activity are of paramount importance but also complex since they include transcriptional, post-transcriptional, translational and post-translational processes.14 Various processes regulate the constitutive isoforms of the NOS at the post-translational level. The first process relies on the control of enzyme activity by the intracellular concentration of calcium. In this respect, the triggering of NMDA (N-methyl-D-aspartate) receptors (NMDAR) by glutamate may result in the entry of calcium which, after binding with calmodulin, activates the nNOS isoform (Fig. 2). In blood vessels, acetylcholine, after binding to muscarinic receptors located on endothelial cells, may activate phospholipase C which in turn stimulates calcium entry, leading to eNOS activation. NO produced through the above processes then diffuses freely—irrespective of the presence of membranes—into adjacent cells. Phosphorylation/ dephosphorylation processes involving protein kinases dependent on cyclic adenosine monophosphate, cyclic guanosine monophosphate (cGMP) and calcium/calmodulin, and disparate phosphatases14 also control the constitutive isoforms of NOS. The influence of phosphorylation on the enzyme activity still remains unclear, since it has been reported as being decreased, increased or unaffected.10 However, it has been recently reported that glutamate can dose-dependently reverse nNOS phosphorylation induced by NMDAR.15 Thus, it is possible that phosphorylation/dephosphorylation processes contribute—through the intensity of the glutamatergic stimulus—to the maintenance of either a normal concentration (physiological situation) or

Figure 1 Schemas of the structural domains of NOS homodimer (A) and of the overall biochemical reactions related to NO production (B). Abbreviations: Arg, L-arginine; BH4, tetrahydrobiopterin; CaM, calmodulin; FAD, flavin adenine dinucleotide; FMN, flavin mononucleotide; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form.

NO and sleep

Figure 2 Glutamate stimulation of NMDA receptor triggering calcium influx for nNOS activation. Abbreviations: CaM, calmodulin; Glu, glutamate; nNOS, neuronal nitric oxide synthase; NMDA-receptors, N-methyl-Daspartate receptor; PDZ, conserved protein domain; PSD-95, post-synaptic density 95 protein.

a neurotoxic concentration (glutamate-dependent neurotoxicity) of NO. Moreover, interactions between the N-terminal non-catalytic conserved protein domain of nNOS (mediating protein–protein interactions) and those of other proteins may also play a part in the processes mentioned.16,17 iNOS, which is mainly regulated at the transcriptional and post-transcriptional levels, involves agents such as nuclear factor kB (NF-kB), a redox-responsive transcription factor, in the control of its expression. In order to be expressed, this enzyme also requires stimulation by immunological or proinflammatory agents (e.g. bacterial lipopolysaccharide, pro-inflammatory cytokines). Finally, as for constitutive isoforms, interactions between iNOS protein and other proteins have been suggested to influence iNOS activity.18

NOS distribution in the central nervous system Techniques related to histochemistry, immunohistochemistry and in situ hybridization have been used to map NO-ergic and nNOS-positive neurons.

103 nNOS neurons are distributed throughout the entire rat brain encephalon either in a scattered manner or in dense clusters. Telencephalon. Particularly in the cortex, interneurons are labelled throughout cortical layers II–VI. Somatostatin, neuropeptide Y, vasoactive intestinal polypeptide and gamma-aminobutyric acid (GABA) are co-localized within these interneurons. In the hippocampus (mainly area CA1), the labelled elements are again interneurons co-localizing GABA. Positively labelled neurons are also present in the hippocampal dentate gyrus, the amygdala and the striatum. Diencephalon. Positive nNOS neurons are abundant in the hypothalamus (supraoptic and paraventricular nuclei) but scarce in the thalamus, although some are present in the ventro-, medial and suprageniculate bodies. Mesencephalon, pons and medulla. Some catecholaminergic neurons have been observed in the ventral tegmental area of the mesencephalon. However, the densest populations of nNOS neurons have been described in the pons and mainly in the laterodorsal and pedunculopontine tegmental nuclei (LDT, PPT). These neurons, covering the areas involved in the genesis of rapid-eye-movements (REM) sleep,19,20 also co-localize acetycholine, substance P and corticotrophin releasing factor.21,22 Moreover, nNOS is present in serotoninergic neurons of the rostral raphe (dorsal and medial) but is lacking in the caudal groups.23 Generally, catecholaminergic neurons do not contain nNOS, although some positively labelled neurons are present in the lateral part of the pontin reticular nucleus. Cerebellum. The highest levels of nNOS protein are found in the cerebellum, particularly in granule cells. In the deep molecular layers, basket cells are also stained.21,24,25 The eNOS isoform is predominantly located in the endothelial cells of cerebral vessels but may also be present in other brain cells.26 iNOS, induced mainly in glial cells, is also reportedly expressed in neurons following inflammatory processes and neurodegeneration.27 Finally, all NOS isoforms are expressed in brain tissue throughout ageing and associated pathologies.5,6,26,28

Molecular targets for NO The main physiological target clearly identified for NO is soluble guanylate cyclase (sGC), which is subsequently capable of triggering the overproduction of cGMP. Moreover, histochemical

104 Table 1

S. Gautier-Sauvigne ´ et al. Nitric oxide (NO) and related species.

Common name

Symbol

Nitric oxide Nitrosonium Nitroxylanion Nitrogen dioxide Nitrite Nitrate Peroxynitrite Peroxynitrous acid Dinitrogen trioxide

NO% NOC NOK NO2 NOK 2 NOK 3 ONOOK ONOOH N2O3

and pharmacological approaches have established the complementary distributions of sGC, cGMP and nNOS.29–31 NO, after its release, binds the haem of the sGC to form a ferrous–nitrosyl–haem complex that allows sGC activation. The issued cGMP causes signal transduction via a kinase.32 Another putative target for NO is the cytochrome oxidase. By competing with oxygen for binding this enzyme of the respiratory chain, NO inhibits its activity both specifically and reversibly. This mitochondrial modulation of oxygen consumption thus suggests that NO plays a regulatory role in energy production.33,34 NO is also involved in the formation of adducts on protein residues like N-nitrosamines or S-nitrosothiols. In physiological conditions, these modifications contribute to the regulation of various metabolic processes, including ionic channels gated by NMDARs (S-nitrosylation).35 In addition, the three interrelated redox forms through which NO exists (NOC, NO% and NOK) further allow a cross-reactivity with oxygen, carbon dioxide, hydrogen peroxide, superoxide ion and transition-metal ions.36,37 These conversions lead to the formation of various reactive nitrogen species (RNS) (Table 1), thereby extending the biological reactivity of NO. At moderate concentrations, both RNS and reactive oxygen species (ROS) maintain the redox homeostasis. However, in excess, these compounds can damage the cells (Fig. 3).34,38,39 Among them, peroxynitrites resulting from the cross-reactivity of NO with superoxide ions are deleterious oxidative radicals producing strong oxidation, S-nitrosation, S-thiolation and nitration.40,41 The above radicals are implicated in ageing processes and associated neurodegenerative pathologies.

NO and sleep There is now a large consensus that the intercellular messenger NO is widely implicated in

Figure 3 Main NO-related species involved in nitrosative or oxidative stress. This synthetic schema does not take into account the stoichiometric aspect of biochemical reactions.

the modulation of the sleep–wake states. The main evidence comes from polygraphic recordings combined with general or local pharmacological treatments using either NOS inhibitors or NO donors in animals (Tables 2 and 3). 42 More sophisticated techniques (e.g. voltammetric detection of NO, single-unit recordings) and animal models (iNOS and nNOS knockout mice) provide further support. However, data related to human pathology are also crucial. Polygraphic and pharmacological approaches. Several categories of compounds have been assessed using these approaches. Direct microinjection of the NO precursor L-arginine into the lateral basal forebrain during the light phase did not significantly change the sleep–wake states in rats.43 However, when this compound was delivered intracerebroventricularly during the dark period, slow-wave sleep (SWS) was also enhanced and the waking state reduced.43 Furthermore, when L-arginine was infused during the light phase into the PPT, a nucleus known to be involved in the regulation of sleep states, an increase in SWS predominated.44 Regarding the NO donors, the intracerebroventricular administration of 3-morpholinosydnonimine (molsidomine; SIN-1) or S-nitroso-N-acetyl-DL-penicillamine (SNAP) in rat elicited an increase in SWS.45 The same effect was observed in cat following the local infusion of SNAP into the PPT.46 The effects of nNOS inhibitors

NO and sleep Table 2

105

NOS inhibitors currently used in sleep research.

Common name

Abbreviation

Apparent selectivity for NOS isoformsa

Nu-Monomethy-L-arginine Nu-Nitro-L-arginine Nu-Nitro-L-arginine-methyl ester Nu-Amino-L-arginine Nu-Nu-Dimethyl-L-arginine 7-Nitroindazole Aminoguanidine 2-Amino-5,6-dihydro-6-methyl-4H-1, 3-thiazine

L-NMDA

nNOS, eNOSOiNOS nNOS, eNOS[iNOS nNOS, eNOS, iNOS (O?) nNOS, iNOSOeNOS nNOS, eNOS, iNOS (O?) nNOSOiNOS, eNOS iNOSOeNOS, nNOS iNOS[eNOS, nNOS

L-NA L-NAME L-NAA L-ADMA 7-NI AG AMT

Examination of inhibitory potency and selectivity of commonly used NOS inhibitors give inconsistent in vitro results.42 a Evaluated in vitro or in vivo.

appear less homogenous, since the administration of N u -nitro- L-arginine-methyl ester ( L-NAME; intracerebroventricularly, intravenously, or subcutaneously) or 7-nitro-indazole (7-NI; intraperitoneal) reportedly reduces sleep43,47,48 while intraperitoneal administration of Nu-monomethyl49 50 L-arginine or L-NAME facilitated sleep. However, it must be stressed that the ability of Nu-monomethyl-L-arginine to inhibit NOS implies first a NO genesis.51 The above discrepancies can be explained by the lack of specificity of the inhibitors employed, their difficulty in reaching their brain target,50 the different routes of administration used as well as the great diversity in the time schedules employed for the injections. Polygraphic approaches using voltammetrically controlled compounds. These approaches helped to elucidate the NO–sleep relationships. In a first attempt, properties of the substances used to inhibit or increase the NO release were first checked with voltammetric methods employing an NO-specific sensor,52 after which the influence of the controlled substances on sleep–wake states was analyzed. Results obtained with NO donors such as hydroxylamine,52 S-nitrosoglutathione53 and SIN-154 confirmed that these substances were indeed capable of elevating the brain NO content. Table 3

However, the effects obtained with the intraperitoneal administration of L-NAME were not consistent with the properties previously suggested for this compound. Contrary to L-nitro-arginine-p-nitroanilide (L-NAPNA) and 7-NI, L-NAME administered intraperitoneally did not induce significant changes in the NO voltammetric signal measured in the rat cortex.50 We emphasize this aspect, since L-NAME is widely used in laboratories and this result might reflect a peripheral effect when so administered. One possible explanation for the absence of an L-NAME effect is its difficulty in reaching nNOS when administered through a single injection.50 It is therefore possible that an iterative procedure55 or subcutaneous administrations47 would increase its accessibility to the brain. Whatever the particularities of the possible mechanisms involved, in our experimental conditions (single intraperitoneal dose of 100 mg/kg), L-NAME appears active mainly in the periphery50 where it can induce an hypertensive vasoconstriction of the vascular system56 but also impair the NO-ergic systems driving peripheral stimuli to the brain through vagoaortic nerves and the tractus solitarius.57 Stimulation of vagoaortic nerves58 and lesioning the tractus solitarius59 are reported to facilitate sleep despite the existence of atypical changes in arterial pressure.

NO donors.

Common name

Abbreviation

Some properties

Sodium nitroprusside

SNP

S-Nitrosoglutathione S-Nitroso-N-acetyl-DL-penicillamine 3-Morpholinosydnonimine (molsidomine) Diethylamine NONOate

GSNO SNAP SIN-1 DEA/NO

A nitrate requiring metabolic pathway for NO release Acts as NO transporter Spontaneous NO release in aqueous solution May release superoxide radicals Nucleophilic compounds releasing NO in aqueous solution or enabling NO adducts

Dipropylenetriamine NONOate Diethylaminotriamine NONOate

DPT/NO DETA/NO

106 The contribution of peripheral and neuronal NO fractions to sleep–wake states was studied using substances controlled by voltammetry. The peripheral inhibitor L-NAME, when injected intraperitoneally, was capable of inducing a significant increase in SWS and REM sleep (Fig. 4) while the nNOS inhibitor 7-NI, also administered intraperitoneally, induced a specific decrease in REM sleep.50 Thus, the sleepfacilitating effects of L-NAME indicate that NO generated in the periphery can inhibit sleep. However, the sleep-inhibiting effects observed with 7-NI, together with its good specificity for nNOS,60 strongly suggest that NO contained in the brain facilitates sleep, particularly REM sleep.50 Local injection of NOS inhibitors and NO donors. The overlapping of nNOS-positive neuronal sets and structures involved in sleep genesis19–21 lead to several approaches involving localized brain injections. It has been reported that the microinjection of L-NAPNA, L-NA, or L-NAME within LDT and PPT reduced SWS and REM sleep.44,46,55 Analogous results were also obtained with 7-NI and L-NAME administered within the dorsal raphe nucleus (nRD; Fig. 5)47,50 or with L-NAME administered within the areas containing sleep neuronal net-

S. Gautier-Sauvigne ´ et al. works.43,45 Thus when nNOS inhibitors are administered adequately they lead to constant modifications in the sleep–wake states (reduction in SWS and REM sleep), again suggesting a sleepfacilitating role for NO in the brain. It can be further argued that although it is difficult for peripherally administered L-NAME to affect brain nNOS, local administration of L-NAME does inhibit nNOS and influence sleep as is the case for more specific inhibitors such as 7-NI.50 Finally, local injections of NO donors like SNAP in the PPT or SIN-1 in the nRD (Fig. 6) increase SWS and REM sleep46 or REM sleep alone.50 These data further confirm that the brain fraction of NO synthesized within the neuronal sets forming part of the sleep anatomical network facilitates sleep. Role of NO in neuronal activity and homeostatic processes. Some studies have further investigated the basic mechanisms involved in the neuronal sets contributing to sleep triggering and maintenance. LDT cholinergic neurons, also known for expressing nNOS21 and for exhibiting a high firing rate during REM sleep,19 were suggested to release NO from their somatodendritic system.61 It is likely that such a paracrine release could control

Figure 4 Effects of the intraperitoneal administration of L-NAME (100 mg/kg) on slow-wave sleep (SWS) and rapid-eyemovements (REM) sleep in the rat. Left part: SWS and REM sleep amounts obtained during the 12 h of the dark period either after vehicle or L-NAME injections. Duration is expressed in minutes (meanGSEM) on ordinates and hourly on abscissae. Right part: duration after L-NAME is expressed as a percentage (meanGSEM) relative to saline-injected animals. Abbreviations: n, animal number; h, hours; stars indicate the level of significance: *p!0.05; **p!0.01 (from reference 50).

NO and sleep

107

Figure 5 Local injections of L-NAME (100 ng/0.2 ml) in the nRD (nucleus raphe dorsalis) of the rat brain. (A) Schematic representation of the sites injected (stars indicate effective sites in frontal section, while squares show the non-efficient ones). (B) Left part: REM sleep amounts obtained during the 12 h of the dark period either after vehicle or L-NAME injections. Duration is expressed in minutes (meanGSEM) on ordinates and hourly in abscissae. Right part: duration after L-NAME is expressed as a percentage (meanGSEM) relative to saline-injected animals. Abbreviations: n, number of injections; h, hours; AP, anteroposterior; stars indicate the level of significance: *p!0.05; **p!0.01 (from reference 50).

(through an auto-inhibitory process) the discharge rate of the neurons as well as the release of neurotransmitters from axonal nerve endings. The enhancement of NO release evidenced in the thalamus,62 an area poor in NOS-positive perikarya

but receiving input from the pontine tegmentum,62 might depend on the regulatory processes taking place in the pons. NO also regulates the release of acetylcholine and consequently the occurrence of REM sleep since

Figure 6 Local injections of SIN-1 (200 ng/0.2 ml) in the nRD of the rat brain. (A) Schematic representation of the sites injected (stars indicate effective sites in frontal sections, while squares show the non-efficient ones). (B) Left part: REM sleep amounts obtained during the 12 h of the dark period either after vehicle or SIN-1 injections. The duration of sleep states is expressed in minutes (meanGSEM) on ordinates and hourly on abscissae. Right part: duration after SIN-1 is expressed as a percentage (meanGSEM) relative to saline-injected animals. Abbreviations: n, number of injections; h, hours; AP, anteroposterior; stars indicate the level of significance: *p!0.05; **p!0.01 (from reference 50).

108 dialyzing an NOS inhibitor (L-NA) in areas containing cholinergic perikarya (PRF, pontine reticular formation; PPT) decreases acetylcholine release together with the amount of REM sleep.63 Changes taking place in acetylcholine release at the level of the axonal nerve endings, where PRF and PPT perikarya impinge, remain to be further investigated. The nRD was also suggested to be involved in sleep regulatory processes,64 through a SWS- and REMsleep-dependent somatodendritic release of serotonin.65 Since nNOS is present within the nRD serotoninergic neurons, their release of NO may also contribute to sleep regulation. In this way, it has been demonstrated that the spontaneous release of NO that occurs within the nRD throughout the sleep– wake cycle is maximal during REM sleep.66 In addition, microinjections of NOS inhibitors (L-NAME or 7-NI) within this structure decrease long-lasting sleep.43,50 These results support the notion that the nRD NO component is involved in sleep regulation. While the details of the underlying mechanisms remain to be elucidated, an analogy exists with the processes occurring within the LDT, PPT and PRF. It is not excluded that the active release of NO observed in the nRD during sleep acts, in conjunction with the somatodendritic release of serotonin,65 to reduce the firing rate of serotoninergic neurons. Contributions from various other influences including GABA and adenosine are also likely.44 In the basal forebrain, cholinergic transmission varies across the sleep–wake cycle, and a considerable body of data shows cortical activation by acetylcholine originating from basal forebrain neurons. The data indicate that L-NA delivery significantly increases the acetylcholine release in the basal forebrain but does not affect sleep–wake states.67 However, L-NAME injected into the nucleus of the horizontal limb of the diagonal band of Broca (lateral to the site of L-NA delivery) increased the waking state.68 The data presently available appear to show that cholinergic neurons of the basal forebrain, particularly those located in the medial forebrain, contribute to the rhythmic modulation of the cortical EEG.69 However, it is still possible that NO synthesized within these neurons participates in the profile of the NO release reported in the cortex.53 The part played by NO in sleep regulation can probably also be extended to the mechanisms underlying sleep homeostasis. Indeed, experiments conducted with sleep-deprived animals, in which NOS inhibitors were found to reduce the sleep rebound occurring after sleep deprivation, support a homeostatic role for this atypical messenger.70

S. Gautier-Sauvigne ´ et al. Finally, data from transgenic mice possessing targeted disruptions of nNOS or iNOS genes further emphasize the important part played by NO in the regulation of REM sleep.71 These data indicate that REM sleep was substantially shorter in young-adult nNOS knockout mice than in control mice, in perfect keeping with previous suggestions.50 In contrast, in iNOS knockout animals REM sleep was increased relative to control mice. These results thus suggest that nNOS and iNOS play opposite roles in the regulation of REM sleep.

NO and sleep throughout ageing and associated pathological processes In physiological conditions, the constitutive NOSs generate limited amounts of NO which, for signalling, binds preferentially to the haem of the target proteins. NO produced in excess is quickly mopped up by reactions leading to the production of RNS which, together with ROS, contribute to the maintenance of the cellular homeostasis. In contrast, iNOS, up-regulated by inflammatory mediators of the immune system, synthesizes large amounts of NO and, once expressed, remains active for a longer period. While a high enzymatic activity to iNOS is necessary for an effective triggering of the immune defences, its persistent activation may lead to a deleterious overproduction of NO, generating RNS. In these conditions, when the scavenging capacity of anti-oxidants is exceeded, an imbalance in the production of RNS and ROS (i.e. oxidative stress) occurs. Thus, it is not surprising that NO has been closely associated with brain ageing and associated neurodegenerative pathologies, e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease. NO also plays a prominent role in several other pathologies, including depression, stroke, obstructive sleep apnoea, epilepsy and parasitaemia such as trypanosomiasis. Most of these pathologies are associated with sleep disturbances. NO, sleep and ageing. Although an elevated oxidative stress, including iNOS expression, has been reported to occur throughout ageing in animals,72 as yet only limited evidence support a NO contribution in the sleep impairments related to ageing. During ageing, the architecture of the sleep– wake states exhibits changes in duration, nycthemeral distribution and sleep homeostatic process.73 The release of NO reportedly increases in the cortex of older rats while the basal amount of REM sleep decreases. However, REM sleep deprivation leads to only a limited overproduction of NO in the cortex of these animals as compared with adult ones.74

NO and sleep This less efficient release of NO might be associated with their high vulnerability to stress.75 Besides, it is also documented that after bacterial lipopolysaccharide administration, cerebral iNOS expression (like during ageing76) occurs together with REM sleep suppression.76–78 The above evidence of a relationship between NO dynamics and the sleep–wake cycle suggests that the homeostatic regulation of REM sleep is an age-dependent process involving NO. NO, sleep and PD. Patients with PD develop sleep disorders mainly characterized by daytime sleepiness. It is not yet clear if the underlying causes are due to the disease itself or to the side effects of the dopaminergic medication administered. Since some recent reviews have been devoted to this disease and related sleep impairments,79–81 we simply recall here that the sleep architecture and circadian rhythms are impaired in PD patients. Both oxidative stress (NO and related species) and dysregulation of glutathione metabolism are involved in the pathogenesis of the disease. Indeed, several reports suggest that an overproduction of NO,82–85 protein nitrosylation86 and depletion in brain glutathione abolish its protective role against peroxynitrite damage,87–89 and astrocytic and neuronal mitochondria impairments.90 Moreover, extracellular glutathione disulphide, produced from glutathione, has been shown to down-regulate NMDAR stimulation, thus protecting the corresponding neurons from glutamate excitotoxicity.91 Finally, glutathione disulphide has also been reported to promote sleep by inhibiting glutamatergic neurotransmission.92 Although there is no direct experimental evidence, the above data suggest the existence of a link between the sleep profile of PD patients and NO production. NO, sleep and AD. AD patients exhibit alterations in sleep architecture and circadian rhythms that increase with the progression of the disease. While the data available include some peculiarities,93 disturbances generally comprise decreases in REM and non-REM (SWS) sleep, a slowed theta rhythm and a lack of sleep rebound after sleep deprivation.94 These conditions are associated with impairments of sleep-related structures like the loss of cholinergic neurons in LDT, degenerative processes in the nucleus basalis of Meynert and dysfunctions of biological clocks. Glial activation accompanies the neurodegenerative processes in AD and forms the basis of a production of proinflammatory and cytotoxic factors including cytokines and NO.95 Furthermore, b-amyloid, in combination with interferon gamma, triggers the production of RNS, ROS96 and tumour necrosis factor-alpha. Through lipid peroxidation and calcium homeostasis disruption, these complex

109 processes produce metabolic impairments and DNA damage.97,98 Finally, NF-kB, regulating proinflammatory cytokine responses and iNOS activation, also exerts a critical role in sleep regulation.99 As for PD patients, the above data suggest the existence of correlative links between the sleep profile of AD patients and the NO production including the related RNS and ROS. We will not discuss the situation of various other neurodegenerative pathologies (e.g. Huntington’s disease, amyotrophic lateral sclerosis, Wilson’s disease, dystonia, and Friedreich’s ataxia) since only correlative situations between sleep and NOrelated free radicals are encountered. It should be noted that whatever the particularity of the neurodegenerative disease considered, constant impairments—paralleling modifications to the sleep–wake cycle—are reported in free-radical production (glutamate-related excitotoxicity) and energy metabolism. NO, sleep and epilepsy. It is not clear whether NO acts as a pro- or an anti-epileptic substance (i.e. convulsions or absence seizure).100 Studies conducted on the regulatory processes existing between sleep and epilepsy in genetic-absence epilepsy rats using NOS inhibitor (L-arginine-nitroanilide), NO donor (SIN-1) and anti-epileptic drugs (valproate and ethosuximide), suggest that NO prevents absence epilepsy and acts as an antiepileptic substance by facilitating REM sleep. It is also further suggested that the anti-epileptic efficiency of valproate and ethosuximide is due to their ability to release NO. A new track for petit mal might reside in the above findings.54 NO, sleep and sleeping sickness. Human African trypanosomiasis is the life-threatening sleeping sickness provoked by tsetse fly inoculation of Trypanosoma gambiense or Trypanosoma rhodesiense. After inoculation and local multiplication, the parasite invades the blood and lymphatic organs. Its intrusion in the central nervous system follows the haemolymphatic stage. At the stage of meningoencephalitis, among several neurological dysfunctions a prevalent symptom is the progressive disruption of the 24-h distribution of the sleep– wake cycle101 which also appears in rats infected with Trypanosoma brucei brucei. NO appears as a pivotal element in the infection strategy deployed by the trypanosomes leading to haemolymphatic and nervous symptoms of the illness.102 Voltammetric measurements in the brains of rats and mice have revealed increased production of NO due to the inflammatory processes triggered by the trypanosome signalling. In contrast, in rat, mouse and human blood the reduced macrophage NO production observed reflects the strategy deployed

110 by the trypanosome to impair immune processes. Furthermore, the similarity of the NO involvement in blood of humans, rats and mice is an indication that the increases in brain NO observed in animals may also exist in humans and be of the same origin. Finally, according to the part played by NO in the regulatory mechanisms of the circadian clock (suprachiasmatic nuclei), it appears likely that the sleep impairments reported in humans and animals rely on an increase in brain NO content.103

Practice points Studies related to the relationships existing between NO and sleep have indicated the following relevant facts: † NO contained in the brain and mainly in the neuronal sets involved in sleep triggering and maintenance (LDT, PPT) facilitates sleep and particularly REM sleep. † NO contained within LDT neuronal sets modulates the discharge of neurons through an auto-inhibitory process also involving the co-synthesized neurotransmitters, i.e. acetylcholine at least. This process probably adjusts the outflow of neurotransmitters from the axonal nerve endings. † NO synthesized within the cholinergic population of neurons of the basal forebrain, while under control of the LDT, might modulate the spectral components of the EEG instead of the amounts of the various sleep states. † Finally, impairments occurring in the sleep– wake cycle and free radicals (including NO and related species) are reported in various pathologies.

Research agenda Experiments need to be continued in basic and clinical fields: † Brain cellular and molecular mechanisms need to be further investigated. † The part played by NO (which forms the basis of various free-radical species) must be considered in ageing processes and associated neurodegenerative pathologies.

S. Gautier-Sauvigne ´ et al.

Acknowledgements This work was supported by Claude Bernard University, EA 3734. We thank also English Manager Science Editing for improving the English.

References 1. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373–6. 2. McDonald LJ, Murad F. Nitric oxide and cyclic cGMP signaling. Adv Pharmacol 1995;34:263–75. 3. Dawson VL, Dawson TM. Physiological and toxicological actions of NO in the central nervous system. In: Ignarro L, Murad F, editors. Nitric oxide, biochemistry, molecular biology and therapeutic implications. San Diego: Academic press; 1995. p. 323–42. 4. Losonczy GY, Kriston T, Szabo A, Muller V, Harvey J, Hamar P, et al. Male gender predisposes to development of endotoxic shock in the rat. Cardiovasc Res 2000;47:183–91. 5. Law A, O’Donnell J, Gauthier S, Quirion R. Neuronal and inducible nitric oxide synthase expressions and activities in the hippocampi and cortices of young adult, aged cognitively unimpaired, and impaired Long-Evans rats. Neuroscience 2002;112:267–75. 6. Obrenovitch TP, Urenjaka J, Zilkhaa E, Jayb TM. Excitotoxicity in neurological disorders: the glutamate paradox. Int J Dev Neurosci 2000;18:281–7. 7. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 1991;351:714–8. 8. Moncada S, Higgs A, Furchgott R. XIVth. International union of pharmacology nomenclature in nitric oxide research. Pharmacol Rev 1997;49:137–42. 9. Marletta MA. Nitric oxide synthase: aspects concerning structure and catalysis. Cell 1994;78:927–30. 10. Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell 1994;78:915–8. 11. Abu-Soud HM, Stuehr DJ. Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer. Proc Natl Acad Sci USA 1993;90:10769–72. 12. Hurshman AR, Krebs C, Edmondson DE, Marletta MA. Ability of tetrahydropterin analogues to support catalysis by inducible nitric oxide synthase: formation of a pterin radical is required for enzyme catalysis. Biochemistry 2003;42:13287–303. 13. Lowenstein CJ, Snyder SH. Nitric oxide, a novel biologic messenger. Cell 1992;70:705–7. 14. Sase K, Michel T. Expression and regulation of endothelial nitric oxide synthase. Trends Cardiovasc Med 1997;7:28–37. 15. Rameau GA, Chiu LY, Ziff EB. Bidirectional regulation of neuronal nitric oxide synthase phosphorylation at serine 847 by the NMDA receptor. J Biol Chem 2004;279:14307–14. 16. Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and a1syntropin mediated by PDZ domains. Cell 1996;84:757–67.

* The most important references are denoted by an asterisk.

NO and sleep 17. Tomita S, Nicoll RA, Bredt DS. PDZ protein interactions regulating glutamate receptor function and plasticity. J Cell Biol 2001;153:19–24. 18. Zhang W, Kuncewitch T, Yu ZY, Zou L, Xu X, Kone BC. Protein–protein interactions involving inducible NOS. Acta Physiol Scand 2003;179:137–42. 19. Sakai K. Executive mechanisms of paradoxical sleep. Arch Ital Biol 1988;126:239–57. 20. Sakai K, Crochet S, Onoe H. Pontine structures and mechanisms involved in the generation of paradoxical (REM) sleep. Arch Ital Biol 2001;139:93–107. *21. Vincent SR, Kimura H. Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 1992;46: 755–84. 22. Dun NJ, Dun SL, Fo ¨rstermann U. Nitric oxide synthase immunoreactivity in rat pontine medullary neurons. Neuroscience 1994;59:429–45. 23. Le ´ ger L, Gay N, Burlet S, Charnay Y, Cespuglio R. Localization of nitric oxide-synthesizing neurons sensing projections to the dorsal raphe nucleus of the rat. Neurosci Lett 1998;257:147–50. 24. Hope BT, Michael GJ, Knigge KM, Vincent SR. Neuronal NADPH-diaphorase is a nitric oxide synthase. Proc Natl Acad Sci USA 1991;88:2811–4. *25. Bredt DS, Snyder SH. NO, a novel neuronal messenger. Neuron 1992;8:3–11. 26. Siles E, Martinez-Lara E, Canuelo A, Sanchez M, Hernandez R, Lopez-Ramos JC, et al. Age-related changes of the nitric oxide system in the rat brain. Brain Res 2002; 956:385–92. 27. Heneka MT, Feinstein DL. Expression and function of inducible nitric oxide synthase in neurons. J Neuroimmunol 2001;114:8–18. 28. Salter M, Knowles RG, Moncada S. Widespread tissue distribution, species distribution and changes in activity of Ca2C-dependent and Ca2C-independent nitric oxide synthases. FEBS Lett 1991;291:145–9. 29. Bredt DS, Snyder SH. Nitric oxide mediates glutamatelinked enhancement of cGMP levels in cerebellum. Proc Natl Acad Sci USA 1989;86:9030–3. 30. Schmidt HHW, Gagne GD, Nakane M, Pollock JS, Miller MF, Murad F. Mapping of neural nitric oxide synthase in the rat suggest frequent co-localization with NADPH diaphorase but not with soluble guanylate cyclase, and novel paraneural functions for nitrinergic signal transduction. Histochem Cytochem 1992;40:1439–56. 31. Southam E, Garthwaite J. The nitric oxide-cyclic GMP signalling pathway in rat brain. Neuropharmacology 1993; 32:1267–77. 32. Denniger JW, Marletta MA. Guanylate cyclase and the %NO/cGMP signaling pathway. Biochem Biophys Acta 1999; 1411:334–50. 33. Beltran B, Mathur A, Duchen MR, Erusalimsky JD, Moncada S. The effect of nitric oxide on cell respiration: a key to understanding its role in cell survival or death. Proc Natl Acad Sci USA 2000;97:14602–7. 34. Stewart VC, Heales SJR. Nitric oxide induced mitochondrial dysfunction: implications for neurodegeneration. Free Radic Biol Med 2003;34:287–303. 35. Choi YB, Tenneti LDA, Ortiz J, Bai G, Chen HSV, Lipton SA. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nytrosylation. Nat Neurosci 2000;3:15–21. 36. Stamler JS, Singel DJ, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science 1992;258: 1898–902. 37. Koppenol WH. The basic chemistry of nitrogen monoxide and peroxinitrite. Free Radic Biol Med 1998;25:385–91.

111 38. Dro ¨ge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47–95. 39. Radi R, Cassina A, Hodara R, Quijano C, Castro L. Peroxynitrite reactions and formation in mitochondria. Free Radic Biol Med 2002;33:1451–64. 40. Squarito GL, Pryor WA. Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med 1998;25:392–402. 41. Wink DA, Mitchell JB. Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 1998;25: 434–56. 42. Boehr R, Ulrich WR, Klein T, Mirau B, Haas S, Baur I. The potency and selectivity of arginine substrate site nitricoxide synthase inhibitors is solely determined by their affinity toward the different isoenzymes. Mol Pharmacol 2000;58:1026–34. *43. Monti JM, Jantos H. Microinjections of the nitric oxide synthase inhibitor L-NAME into the lateral basal forebrain alters the sleep–wake cycle of the rat. Prog NeuroPsychopharmacol Biol Psychiatry 2004;28:239–47. *44. Hars B. Endogenous nitric oxide in the rat pons promotes sleep. Brain Res 1999;816:209–19. 45. Kapas L, Krueger J. Nitric oxide donors SIN-1 and SNAP promote non-rapid-eye-movement sleep in rats. Brain Res Bull 1996;41:293–8. *46. Datta S, Patterson EH, Siwek DF. Endogenous and exogenous nitric oxide in the pedunculopontine tegmentum induces sleep. Synapse 1997;27:69–78. 47. Monti JM, Jantos H, Monti D. Increase of waking and reduction of NREM and REM sleep after nitric oxide synthase inhibition: prevention with GABAA or adenosine A1 receptors agonists. Behav Brain Res 2001;123:23–5. 48. Dzoljic MR, Van Leeuwen R, De Vries R. Sleep and nitric oxide: effects of 7-nitro indazole-inhibitor of brain nitric oxide synthase. Brain Res 1996;718:145–50. 49. Dzoljic MR, De Vries R. Nitric oxide synthase inhibition reduces wakefulness. Neuropharmacology 1994; 33:1505–9. *50. Burlet S, Le ´ger L, Cespuglio R. Nitric oxide and sleep in the rat: a puzzling relationship. Neuroscience 1999;92: 627–39. 51. Olken NM, Marletta MA. NG-Methyl-L-arginine functions as an alternate substrate and mechanism-based inhibitor of nitric oxide synthase. Biochemistry 1993;32: 9677–85. *52. Cespuglio R, Burlet S, Marinesco S, Robert F, Jouvet M. Brain voltammetric detection of nitric oxide in the rat. CRAS (Paris) 1996;319:191–200. *53. Burlet S, Cespuglio R. Voltammetric detection of nitric oxide (NO) in the rat brain: its variations through the sleep– wake cycle. Neurosci Lett 1997;226:131–5. 54. Faradji H, Rousset C, Debilly G, Vergnes M, Cespuglio R. Sleep and epilepsy: a key role for nitric oxide? Epilepsia 2000;41:794–801. 55. Kapa `s L, Fang J, Krueger JM. Inhibition of nitric oxide synthesis inhibits rat sleep. Brain Res 1994;664:189–96. 56. Rees DD, Palmer RMJ, Schulz R, Hodson HF, Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol 1990; 101:746–52. 57. Ruggiero DA, Mtui EP, Otake K, Anwar M. Central and primary visceral afferents to nucleus tractus solitarii may generate nitric oxide as a membrane-permeant neuronal messenger. J Comp Neurol 1996;364:51–67. 58. Puizillout JJ, Gaudin-Chazal G, Bras H. Vagal mechanisms in sleep regulation. Exp Brain Res 1984;8:19–38.

112 59. Nosjean A, Arluison M, Laguzzi RF. Increase in paradoxical sleep after destruction of serotoninergic innervation in the nucleus tractus solitarius of the rat. Neuroscience 1987;23: 469–81. 60. Moore PK, Babbedge RC, Wallace P, Gaffen ZA, Hart SL. 7-Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti-nociceptive activity in the mouse without increasing blood pressure. Br J Pharmacol 1993; 108:296–7. *61. Leonard CS, Michaelis EK, Mitchell KM. Activity-dependent nitric oxide concentration dynamics in the laterodorsal tegmental nucleus in vitro. J Neurophysiol 2001;86: 2159–72. 62. Williams JA, Vincent SR, Reiner PB. Nitric oxide production in rat thalamus changes with behavioral state, local depolarisation, and braistem stimulation. J Neurosci 1997;17:420–7. *63. Leonard TO, Lydic R. Pontine nitric oxide modulates acetylcholine release, rapid eye movement sleep generation, and respiratory rate. J Neurosci 1997;17: 774–85. 64. Jouvet M. The role of monoamines and acetylcholine containing neurons in the regulation of the sleep-waking cycle. Ergebn der Physiol 1972;100:166–307. 65. Cespuglio R, Houdouin F, Oulerich M, El Mansari M, Jouvet M. Axonal and somatodendritic modalities of serotonin release: their involvement in sleep preparation, triggering and maintenance. J Sleep Res 1992;1:150–6. 66. Cespuglio R, Debilly G, Burlet S. Cortical and pontine variations occurring in the voltammetric NO signal throughout the sleep–wake cycle in the rat. Arch Ital Biol 2004;142:551–56. 67. Vasquez J, Lydic R, Baghdoyan HA. The nitric oxide synthase inhibitor N-nitro-L-arginine increases basal forebrain acetylcholine release during sleep and wakefulness. J Neurosci 2002;22:5597–605. 68. Monti JM, Hantos H, Ponzoni A, Monti D, Banchero P. Role of nitric oxide in sleep regulation: effects of L-NAME, an inhibitor of nitric oxide synthase, on sleep in rats. Behav Brain Res 1999;100:197–205. 69. Marino J, Cudeiro J. Nitric oxide-mediated cortical activation: a diffuse wake-up system. J Neurosci 2003;23: 4299–307. 70. Ribeiro AC, Gilligan JC, Kappas L. Systemic injection of a nitric oxide synthase inhibitor suppresses sleep responses to sleep deprivation in rats. Am J Physiol Regul Integr Comp Physiol 2000;278:1048–56. 71. Chen L, Madje JA, Krueger JM. Spontaneous sleep in mice with targeted disruptions of neuronal or inducible nitric oxide synthase genes. Brain Res 2003;973:214–22. 72. Butterfield DA, Howard B, Yatin S, Koppal T, Drake J, Hensley K, et al. Elevated oxidative stress in models of normal brain aging and Alzheimer’s disease. Life Sci 1999; 65:1883–92. 73. Borbe ´ly AA, Ackermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms 1999;14:557–68. 74. Cle ´ment P, Gharib A, Cespuglio R, Sarda N. Changes in the sleep–wake cycle architecture and cortical release during ageing in the rat. Neuroscience 2003;116:863–70. 75. Cespuglio R, Marinesco S, Baubet V, Bonnet C. Evidence for a sleep promoting influence of stress. Adv Neuroimmunol 1995;5:145–54. 76. Harada S, Imaki T, Chikada N, de Naruse M, Demura H. Distinct distribution and time-course changes in neuronal nitric oxide synthase and inducible NOS in the paraventricular nucleus following lipopolysaccharide injection. Brain Res 1999;821:322–32.

S. Gautier-Sauvigne ´ et al. 77. Wakita T, Shintani F, Yagi G, Asa M, Nozawa S. Combination of inflammatory cytokines increases nitrite and nitrate levels in the paraventricular nucleus of conscious rats. Brain Res 2001;905:12–20. 78. Schiffelhilz T, Lancel M. Sleep changes induced by lipopolysaccharide in the rat are influenced by age. Am J Physiol Regul Integr Comp Physiol 2001;280:398–403. 79. Garcia-Borreguero D, Larrosa O, Bravo M. Parkinson’s disease and sleep. Sleep Med Rev 2003;7:115–29. 80. Clarenbach P. Parkinson’s disease and sleep. J Neurol 2000; 247(Suppl IV):20–3. 81. Scha ¨fer D, Greulich W. Effects of parkinsonian medication on sleep. J Neurol 2000;247(Suppl IV):24–7. 82. Hirrlinger J, Schulz JB, Dringen R. Effects of dopamine on the glutathione metabolism of cultured astroglial cells: implications for Parkinson’s disease. J Neurochem 2002;82: 458–67. 83. Schulz JB, Matthews RT, Beal MF. Role of nitric oxide in neurodegenerative diseases. Curr Opin Neurol 1995;8: 480–6. 84. Hunot S, Boissiere F, Faucheux B, Brugg B, Mouattprigent A, Agid Y, Hirsch EC. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience 1996;72: 355–63. 85. Liberatore GT, Jakson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 1999;5:1403–9. 86. Giasson BI, Duda JE, Murray IVJ, Chen QP, Souza JM, Hurtig HI, et al. Oxidative damage linked to neurodegeneration by selective a-synuclein nitration in synucleinopathy lesions. Science 2000;290:985–9. 87. Barker JE, Bolanos JP, Land JM, Clark JB, Heales SRJ. Gluthathione protects astrocytes from peroxynitritemediated mitochondrial damage: implications for neuronal/astrocytic trafficking and neurodegeneration. Dev Neurosci 1996;18:391–6. 88. Jenner P, Dexter DT, Sian J, Schapira AHV, Marsden CD. Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental Lewy body disease. Ann Neurol 1992;32:S82–S87. 89. Merad-Boudia M, Nicole A, Santiard-Baron D, Saille C, Ceballos-Picot I. Mitochondrial impairment as an early event in the process of apoptosis induced by gluthathione depletion in neuronal cells: relevance to Parkinson’s disease. Biochem Pharmacol 1998;56:645–55. 90. Shapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990;54:823–7. 91. Sucher NJ, Lipton SA. Redox modulatory site of the NMDA receptor channel complex: regulation by oxidized gluthathione. J Neurosci Res 1991;30:582–91. 92. Honda K, Komoda Y, Inoue ´ S. Oxidized glutathione regulates physiological sleep in unrestrained rats. Brain Res 1994;636:253–8. 93. Schenck CH, Garcia-Rill E, Skinner RD, Anderson ML, Mahowald MW. A case of REM sleep behavior disorder with autopsy-confirmed Alzheimer’s disease: postmortem brain stem histochemical analyses. Biol Psychiatry 1996;40: 422–5. 94. Autret A, Lucas B, Mondon K, Hommet C, Corcia P, Saudeau D, Toffol B. Sleep and brain lesions: a critical review of the literature and additional new cases. Neurophysiol Clin 2001;31:356–75. 95. Lee J, Chan SL, Mattson MP. Adverse effect of a preneselin1 mutation in microglia results in enhanced nitric oxide

NO and sleep

96.

97. 98.

99. 100.

101.

102.

103.

and inflammatory cytokine responses to immune challenge in the brain. Neuromol Med 2002;2:29–45. Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD. Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42 and lipopolysaccharide-activated microglia. J Neurosci 2002;22:3484–92. Beal MF. Energetics in the pathogenesis of neurodegenerative diseases. TIBS 2000;23:298–304. Akama KT, Albanese C, Pestell RG, Van Eldik LJ. Amyloid b peptide stimulates nitric oxide production in astrocytes through an NF-kB-dependent mechanism. Proc Natl Acad Sci USA 1998;95:5795–800. Krueger JM, Majde JA, Ferenc Jr O. Sleep in host defense. Brain Behav Immun 2003;17:S41–S47. Buisson A, Lakhmeche N, Verrecchia C, Plotkine M, Boulo RG. Nitric oxide: an endogenous anticonvulsant substance. Neuroreport 1993;4:444–6. Buguet A, Gati R, Sevre JP, Develoux M, Bogui P, Lonsdorfer J. 24-h polysomnographic evaluation in a patient with sleeping sickness. Electroencephalogr Clin Neurophysiol 1989;72:471–8. Buguet A, Vincendeau P, Bouteille B, Burlet S, Cespuglio R. Nitric oxide in murine malaria: divergent roles in blood and brain suggested by voltammetric measures. Trans R Soc Trop Med Hyg 1999;93:663–4. Buguet A, Bourdon L, Bouteille B, Cespuglio R, Vincendeau P, Radomski MW, Dumas M. The duality of sleeping sickness: focusing on sleep. Sleep Med Rev 2001;5: 139–53.

113 Glossary of terms

cGMP: cyclic guanosine monophosphate GABA: gamma-aminobutyric acid LDT: laterodorsal tegmentum u L-NA: N -nitro-L-arginine u L-NAME: N -nitro-L-arginine-methyl ester L-NAPNA: L-nitro-arginine-p-nitro-anilide NF-kB: nuclear factor Kappa B 7-NI: 7-nitro-indazole NMDA: N-methyl-D-aspartate NMDAR: N-methyl-D-aspartate receptors NO: nitric oxide NOS: NO synthase nNOS, eNOS, iNOS: neuronal, endothelial and inducible isoforms of NOS nRD: dorsal raphe nucleus PPT: pedunculopontine tegmentum PRF: pontine reticular formation REM sleep: rapid-eye-movements sleep RNS: reactive nitrogen species ROS: reactive oxygen species sGC: soluble guanylate cyclase SIN-1: 3-morpholinosydnonimine (molsidomine) SNAP: S-nitroso-N-acetyl-DL-penicillamine SWS: slow-wave sleep (synonym of NREM sleep)