Prostaglandin D(2) is crucial for seizure suppression and postictal sleep.

Epilepsy is a neurological disorder with the occurrence of seizures, which are often accompanied by sleep. Prostaglandin (PG) D2 is produced by hematopoietic or lipocalin-type PGD synthase (H- or L-PGDS) and involved in the regulation of physiological sleep. Here, we show that H-PGDS, L/H-PGDS or DP1 receptor (DP1R) KO mice exhibited more intense pentylenetetrazole (PTZ)-induced seizures in terms of latency of seizure onset, duration of generalized tonic-clonic seizures, and number of seizure spikes.

Elevated CSF histamine levels in multiple sclerosis patients.

Background: Histamine is an ubiquitous inflammatory mediator of numerous physiological processes. Histamine and its receptors have been implicated in multiple sclerosis (MS) disease pathogenesis. We prospectively enrolled 36 MS patients and 19 age and gender-matched healthy volunteers for cerebrospinal fluid (CSF) histamine analysis.

Prostaglandin D2 and sleep/wake regulation.

Prostaglandin (PG) D2 is the most potent endogenous sleep-promoting substance. PGD2 is produced by lipocalin-type PGD synthase localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain, and is secreted into the cerebrospinal fluid as a sleep hormone. PGD2 stimulates DP1 receptors localized in the leptomeninges under the basal forebrain and the hypothalamus.

Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens.

Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosine A(2A) receptors (A(2A)Rs) in the brain, but the specific neurons on which caffeine acts to produce arousal have not been identified. Using selective gene deletion strategies based on the Cre/loxP technology in mice and focal RNA interference to silence the expression of A(2A)Rs in rats by local infection with adeno-associated virus carrying short-hairpin RNA, we report that the A(2A)Rs in the shell region of the nucleus accumbens (NAc) are responsible for the effect of caffeine on wakefulness.

The role of adenosine in the regulation of sleep.

This paper presents an overview of the current knowledge about the role of adenosine in the sleep-wake regulation with a focus on adenosine in the central nervous system, regulation of adenosine levels, adenosine receptors, and manipulations of the adenosine system by the use of pharmacological and molecular biological tools. The endogenous somnogen prostaglandin (PG) D(2) increases the extracellular level of adenosine under the subarachnoid space of the basal forebrain and promotes physiological sleep. Adenosine is neither stored nor released as a classical neurotransmitter and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides.

Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep.

Adenosine has been proposed to promote sleep through A(1) receptors (A(1)R's) and/or A(2A) receptors in the brain. We previously reported that A(2A) receptors mediate the sleep-promoting effect of prostaglandin D(2), an endogenous sleep-inducing substance, and that activation of these receptors induces sleep and blockade of them by caffeine results in wakefulness. On the other hand, A(1)R has been suggested to increase sleep by inhibition of the cholinergic region of the basal forebrain.

Prostaglandins and adenosine in the regulation of sleep and wakefulness.

Prostaglandin (PG) D2 and adenosine are potent humoral sleep-inducing factors that accumulate in the brain during prolonged wakefulness. PGD2 is produced in the brain by lipocalin-type PGD synthase, which is localized mainly in the leptomeninges, choroid plexus and oligodendrocytes, and circulates in the cerebrospinal fluid as a sleep hormone. It stimulates DP1 receptors on leptomeningeal cells of the basal forebrain to release adenosine as a paracrine signaling molecule to promote sleep.

Lipocalin-type prostaglandin D synthase produces prostaglandin D2 involved in regulation of physiological sleep.

Prostaglandin (PG) D2 has been proposed to be essential for the initiation and maintenance of the physiological sleep of rats because intracerebroventricular administration of selenium tetrachloride (SeCl4), a selective inhibitor of PGD synthase (PGDS), was shown to reduce promptly and effectively the amounts of sleep during the period of infusion. However, gene knockout (KO) mice of PGDS and prostaglandin D receptor (DP1R) showed essentially the same circadian profiles and daily amounts of sleep as wild-type (WT) mice, raising questions about the involvement of PGD2 in regulating physiological sleep. Here we examined the effect of SeCl4 on the sleep of WT and KO mice for PGDS and DP1R and that of a DP1R antagonist, ONO-4127Na, on the sleep of rats.

Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice.

Histaminergic neurons play an important role in the regulation of sleep-wake behavior through histamine H(1) receptors (H(1)R). Blockade of the histamine H(3) receptor (H(3)R) is proposed to induce wakefulness by regulating the release of various wake-related transmitters, not only histamine. In the present study, we characterized sleep-wake cycles of H(1)R knockout (KO) mice and their arousal responses to an H(3)R antagonist.

The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus.

Recent research has shown that neurons in the ventrolateral preoptic nucleus are crucial for sleep by inhibiting wake-promoting systems, but the process that triggers their activation at sleep onset remains to be established. Since evidence indicates that sleep induced by adenosine, an endogenous sleep-promoting substance, requires activation of brain A(2A) receptors, we examined the hypothesis that adenosine could activate ventrolateral preoptic nucleus sleep neurons via A(2A) adenosine receptors in rat brain slices. Following on from our initial in vitro identification of these neurons as uniformly inhibited by noradrenaline and acetylcholine arousal transmitters, we established that the ventrolateral preoptic nucleus comprises two intermingled subtypes of sleep neurons, differing in their firing responses to serotonin, inducing either an inhibition (Type-1 cells) or an excitation (Type-2 cells).

Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine.

Caffeine, a component of tea, coffee and cola, induces wakefulness. It binds to adenosine A1 and A2A receptors as an antagonist, but the receptor subtype mediating caffeine-induced wakefulness remains unclear. Here we report that caffeine at 5, 10 and 15 mg kg(-1) increased wakefulness in both wild-type mice and A1 receptor knockout mice, but not in A2A receptor knockout mice.

An adenosine A receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats.

The adenosine A(2A) receptor (A(2A)R) has been demonstrated to play a crucial role in the regulation of the sleep process. However, the molecular mechanism of the A(2A)R-mediated sleep remains to be elucidated. Here we used electroencephalogram and electromyogram recordings coupled with in vivo microdialysis to investigate the effects of an A(2A)R agonist, CGS21680, on sleep and on the release of histamine and GABA in the brain.

Genes for prostaglandin d synthase and receptor as well as adenosine A2A receptor are involved in the homeostatic regulation of nrem sleep.

(1) Prostaglandin D2 is essential for the maintenance of the sleep state. (2) The adenosine and A2A receptor system is a link between the humoral and neural mechanisms of sleep-wake regulation. (3) Prostaglandin D2 plays a crucial role in the homeostatic regulation of NREM sleep.

[Functional analyses of lipocalin-type and hematopoietic prostaglandin D synthases].

Prostaglandin (PG) D synthase (PGDS) catalyzes the isomerization of PGH(2) to PGD(2), which acts as an endogenous somnogen and an allergic mediator. There are two distinct types of PGDS: one is lipocalin-type PGDS (L-PGDS) localized in the central nervous system, male genitals, and heart; and the other is hematopoietic PGDS (H-PGDS) in mast cells and Th2 lymphocytes. L-PGDS is the same as beta-trace, a major protein in human cerebrospinal fluid, and is also secreted into the seminal plasma and plasma.

Dominant localization of adenosine deaminase in leptomeninges and involvement of the enzyme in sleep.

Adenosine is an endogenous hypnotic molecule. However, the mechanism by which the level of extracellular adenosine is regulated remains to be elucidated. We found by Northern hybridization and enzyme assay that ecto-5(')-nucleotidase and adenosine deaminase (ADA), major enzymes responsible for the production and degradation of adenosine, respectively, were localized most abundantly in the leptomeninges within the rat brain.

Prostaglandin E2 activates the histaminergic system via the EP4 receptor to induce wakefulness in rats.

Prostaglandin (PG)E2 promotes the wakeful state when administered into the posterior hypothalamus, in which the histaminergic tuberomammillary nucleus (TMN) is located. To explore the neurotransmitter mechanisms responsible for PGE2-induced wakefulness in rats, we examined the effect of PGE2 on the activity of the histaminergic system and the involvement of PGE2 receptor subtypes in the response. PGE2 perfusion in the TMN at doses of 100, 200, and 400 pmol/min for 2 hr significantly increased histamine release from the medial preoptic area and frontal cortex in a dose-dependent manner, as measured by in vivo microdialysis.

Cloning, expression, crystallization, and preliminary X-ray analysis of recombinant mouse lipocalin-type prostaglandin D synthase, a somnogen-producing enzyme.

Lipocalin-type prostaglandin D synthase is the key enzyme for the production of prostaglandin D(2), a potent endogenous somnogen, in the brain. We cloned, produced, and crystallized the native enzyme and selenomethionyl Cys(65)Ala mutants of the recombinant mouse protein by the hanging drop vapor-diffusion method with both malonate and citrate as precipitants. The native crystals obtained with malonate belong to orthorhombic space group P2(1)2(1)2(1) with lattice constants a = 46.