Role of Adenosine Kinase Inhibitor in Adenosine Augmentation Therapy for Epilepsy: A Potential Novel Drug for Epilepsy.

Epilepsy, an ancient disease, is defined as an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Antiepileptic drugs (AEDs) are currently used as first-line treatment for patients with epilepsy; however, around 36% of patients are diagnosed with refractory epilepsy, which means two or more AEDs have been considered as failed after sufficiently correct usage. Unfortunately, it is unlikely that the improvement of the efficacy of AEDs will be easily achieved, especially since no AEDs show efficacy in ceasing epileptogenesis. Consequently, several endogenous anticonvulsants attract investigators and epileptologists, such as galanin, cannabis, and adenosine. Astrogliosis is a neuropathological hallmark of epilepsy, whatever the etiology is, and astrogliosis is frequently associated with overexpression of adenosine kinase, which means downregulation of synaptic levels of adenosine. Consequently, adenosine is negatively regulated by adenosine kinase through the astrocyte-based cycle. On the other hand, focal adenosine augmentation therapy, using adenosine kinase inhibitor, has been proved to be effective for reducing seizures in both animal models and in vitro human brain tissue resected from a variety of etiology of refractory epilepsy patients. In addition to reducing seizures, adenosine augmentation therapy can also palliate co-morbidities, like sleep, cognition, or depression. Of importance, transgenic mice with reduced ADK were resistant to epileptogenesis induced by acute brain injury. In terms of translation, based on findings of adenosinerelated epileptogenic mechanisms, the application into clinical practice seems to be feasible by molecular strategies that have been already experimentally implemented, including gene and RNA interference. In the present review, we will focus on the evidence of ADK dysfunction in the epileptic brain from human beings and animals, and review the role of ADK inhibitor in adenosine augmentation therapy and the underlying mechanism of prevention of epileptogenesis.

Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics.

Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.

Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect.

OBJECTIVE: In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y12-receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia-reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS). APPROACH AND RESULTS: Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion. Area at risk was assessed by blue dye and IS by 2,3,5-triphenyl-tetrazolium-chloride. Cyclooxygenase-2 (COX2) enzyme activity was assessed by ELISA and expression by real-time polymerase chain reaction. Mechanism responsible was explored using adenosine-receptor antagonist (CGS15943, an A2A/A1 antagonist) or cyclooxygenase inhibition by either aspirin (5, 10, or 25 mg/kg) or specific cyclooxygenase-1 (SC560) or COX2 (SC5815) inhibitors. Ticagrelor, dose-dependently, reduced IS, whereas clopidogrel had no effect. Adenosine-receptor antagonism blocked the ticagrelor effect and COX2 inhibition by SC5815, or high-dose aspirin attenuated the IS-limiting effect of ticagrelor, whereas cyclooxygenase-1 inhibition or low-dose aspirin had no effect. Ticagrelor, but not clopidogrel, upregulated COX2 expression and activity. Also this effect was blocked by adenosine-receptor antagonism. Ticagrelor, but not clopidogrel, increased Akt and endothelial nitric oxide synthase phosphorylation. CONCLUSIONS: Ticagrelor, but not clopidogrel, reduces myocardial IS. The protective effect of ticagrelor was dependent on adenosine-receptor activation with downstream upregulation of endothelial nitric oxide synthase and COX2 activity.

Thalamic synaptic transmission of sensory information modulated by synergistic interaction of adenosine and serotonin.

The thalamic synapses relay peripheral sensory information to the cortex, and constitute an important part of the thalamocortical network that generates oscillatory activities responsible for different vigilance (sleep and wakefulness) states. However, the modulation of thalamic synaptic transmission by potential sleep regulators, especially by combination of regulators in physiological scenarios, is not fully characterized. We found that somnogen adenosine itself acts similar to wake-promoting serotonin, both decreasing synaptic strength as well as short-term depression, at the retinothalamic synapse. We then combined the two modulators considering the coexistence of them in the hypnagogic (sleep-onset) state. Adenosine plus serotonin results in robust synergistic inhibition of synaptic strength and dramatic transformation of short-term synaptic depression to facilitation. These synaptic effects are not achievable with a single modulator, and are consistent with a high signal-to-noise ratio but a low level of signal transmission through the thalamus appropriate for slow-wave sleep. This study for the first time demonstrates that the sleep-regulatory modulators may work differently when present in combination than present singly in terms of shaping information flow in the thalamocortical network. The major synaptic characters such as the strength and short-term plasticity can be profoundly altered by combination of modulators based on physiological considerations.

Adenosina y control homeostático del sueño. Acciones en estructuras diana de los circuitos de vigilia y sueño / Adenosine and homeostatic control of sleep. Actions in target structures of the sleep-wake circuits

La homeostasis del sueño se manifiesta ante situaciones de vigilia prolongada de forma natural o experimentalmente. En estos casos, se presenta somnolencia (o presión de sueño) y, cuando se permite dormir, hay un rebote del sueño en duración e intensidad que compensa la pérdida del mismo. Entre las moléculas que pueden intervenir en la regulación homeostática del sueño, se encuentra la adenosina, cuyos antagonistas, la cafeína y la teofilina, consume la población humana ampliamente como estimulantes. La adenosina es un factor endógeno resultante del metabolismo del ATP en neuronas y glía que se acumula en el medio extracelular y que es capaz de ejercer acciones reguladoras sobre circuitos del ciclo vigilia sueño. Actúa a través de los receptores purinérgicos A1 y A2. En este trabajo se presenta una revisión de las vías metabólicas de la adenosina cerebral y de su liberación por neuronas y glía, y se exponen las acciones de la adenosina y de sus antagonistas en regiones del sistema nervioso central de naturaleza hipnogénica y relacionadas con la vigilia. Se exponen, además, los mecanismos sinápticos involucrados en estas acciones (AU)

Sleep homeostasis occurs during prolonged wakefulness. Drowsiness and sleep pressure are its behavioral manifestations and, when sleep is allowed, there is a sleep rebound of sufficient duration and intensity to compensate for the previous deprivation. Adenosine is one of the molecules involved in sleep homeostasic regulation. Caffeine and theophylline, stimulants widely consumed by the humans, are antagonists. It is an endogenous factor, resulting from ATP metabolism in neurons and glia. Adenosine accumulates in the extracellular space, where it can exert regulatory actions on the sleep-wakefulness cycle circuits. Adenosine acts through the purinergic receptors A1 and A2. This paper reviews: 1) the metabolic pathways of cerebral adenosine, and the mechanisms of its release by neurons and glia to the extracellular space; 2) the actions of adenosine and its antagonists in regions of the central nervous system related to wakefulness, non-REM sleep, and REM sleep, and 3) the synaptic mechanisms involved in these actions (AU)

[Adenosine and homeostatic control of sleep. Actions in target structures of the sleep-wake circuits]. / Adenosina y control homeostático del sueño. Acciones en estructuras diana de los circuitos de vigilia y sueño.

Sleep homeostasis occurs during prolonged wakefulness. Drowsiness and sleep pressure are its behavioral manifestations and, when sleep is allowed, there is a sleep rebound of sufficient duration and intensity to compensate for the previous deprivation. Adenosine is one of the molecules involved in sleep homeostasic regulation. Caffeine and theophylline, stimulants widely consumed by the humans, are antagonists. It is an endogenous factor, resulting from ATP metabolism in neurons and glia. Adenosine accumulates in the extracellular space, where it can exert regulatory actions on the sleep-wakefulness cycle circuits. Adenosine acts through the purinergic receptors A1 and A2. This paper reviews: 1) the metabolic pathways of cerebral adenosine, and the mechanisms of its release by neurons and glia to the extracellular space; 2) the actions of adenosine and its antagonists in regions of the central nervous system related to wakefulness, non-REM sleep, and REM sleep, and 3) the synaptic mechanisms involved in these actions.

Adenosine signaling promotes regeneration of pancreatic ß cells in vivo.

Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing ß cells is still needed. Using a zebrafish model of diabetes, we screened ~7,000 small molecules to identify enhancers of ß cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of ß cell regeneration was the adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA), which, acting through the adenosine receptor A2aa, increased ß cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating ß cell proliferation during regeneration, NECA had only a modest effect during development. The proliferative and glucose-lowering effect of NECA was confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in ß cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes.

Anticonvulsant effect of aqueous extract of Valeriana officinalis in amygdala-kindled rats: possible involvement of adenosine.

ETHNOPHARMACOLOGICAL RELEVANCE: Valeriana officinalis L. (valerian) root extract has been used as an antiepileptic herbal medicine in Iran. AIM OF THIS STUDY: In the present study the effect of valerian extracts on an experimental model of temporal lobe epilepsy (TLE) was evaluated. Moreover, the involvement of adenosine system in the actions of aqueous extract of valerian was evaluated. MATERIALS AND METHODS: Bipolar stimulating and monopolar recording electrodes were implanted stereotaxically in the right basolateral amygdala of male Sprague-Dawley rats. After kindling, the effect of aqueous (200, 500 and 800 mg/kg; intraperitoneal) and petroleum ether (PE; 50 and 100mg/kg; intraperitoneal) extracts of valerian and CPT (selective A(1) receptor antagonist; 10 and 20 microM; intracerebroventricular) on afterdischarge duration (ADD), duration of stage 5 seizure (S5D) and latency to the onset of bilateral forelimb clonuses (S4L) were measured. The effect of CPT (10 microM) on the response of aqueous extract of valerian (500 mg/kg) was also determined. RESULTS: The results showed that aqueous extract of valerian had anticonvulsant effect. However, PE extract and CPT (20 microM) had proconvulsant effect. Administration of CPT (10 microM) before the administration of aqueous extract decreased the anticonvulsant effect of valerian. CONCLUSIONS: The results showed significant anticonvulsant effect for aqueous but not PE extract of valerian. Moreover, CPT as a selective adenosine A(1) receptor antagonist decreased the anticonvulsant effect of valerian aqueous extract. Therefore, we concluded that part of anticonvulsant effect of valerian probably is mediated through activation of adenosine system.

The impact of purinergic signaling on renal ischemia-reperfusion injury.

BACKGROUND: Adenosine provides renovascular protection in mouse models of ischemia-reperfusion injury (I/RI) through purinergic members of the G protein-coupled receptor family, such as the adenosine 2A receptor (A2AR). Ectonucleotidases CD39 and CD73 are integral vascular and immune nucleotidases that regulate extracellular adenosine signaling. Current investigation of CD39 and CD73 in renal I/RI has primarily focused on their respective roles in ischemic preconditioning. METHODS: In this study, we established a unilateral renal I/RI model and investigated the role of adenosine generation versus nucleotide removal in mediating protection in renal I/RI using mice deficient in CD39, CD73 or A2AR, thereby sequentially disrupting ectonucleotidase cascade and adenosinergic signaling. RESULTS: Compared with wild-type mice, Cd73 null mice showed reduced levels of serum creatinine and urea, apoptosis of renal cells, and histologic damage after I/RI. Deletion of CD39 was associated with severe renal injury. Administration of apyrase, a soluble form of CD39, decreased global apoptosis and I/RI induced renal injury in wild-type mice. Apyrase treatment also improved renal histology to some extent in A2AR null mice. CONCLUSION: The relative protective effect of CD73 deletion in renal I/RI may reflect an effect of AMP accumulation. Deletion of CD39 showed deleterious effects and administration of soluble CD39 exerted renal protection, which is partially mediated by A2AR. The protective effect conferred by apyrase suggests that supplementing CD39 NTPDase activity may be a useful therapeutic strategy in renal transplantation.

Eliminating the antilipolytic adenosine A1 receptor does not lead to compensatory changes in the antilipolytic actions of PGE2 and nicotinic acid.

AIM: We examined whether compensatory changes after adenosine A(1) receptor knockout [A(1)R (-/-)] eliminate the antilipolytic actions mediated by this receptor. METHODS: Lipolysis experiments were performed on adipocytes prepared from the wild type A(1)R (+/+), A(1)R (-/-) and heterozygous mice. Gene expression was assayed with cDNA microarray technique and real-time PCR; protein expression with immunoblotting. RESULTS: The A(1)R was the only adenosine receptor involved in lipolysis. The effects of adenosine deaminase and 2-chloroadenosine were abolished in A(1)R (-/-) mice. The IC(50) value of 2-chloroadenosine doubled from 16.6 to 33.6 nm when half of the A(1)Rs were eliminated. Adrenergic alpha(2) agonists had no effects on lipolysis. Prostaglandin E(2) (PGE(2)) inhibited lipolysis with an IC(50) value of 5.8 nm (4.7-7.2 nm) in the A(1)R (+/+) mice and 10.6 nm (9.0-12.6 nm) in the A(1)R (-/-) mice. Nicotinic acid inhibited lipolysis with an IC(50) value of 0.30 microm (0.19-0.46 microm) in the A(1)R (+/+) mice and 0.24 microm (0.16-0.37 microm) in the A(1)R (-/-) mice. G(i)alpha(1) mRNA was significantly up-regulated in adipose tissue from A(1)R (-/-) mice. However, immunoblotting showed that G(ialpha1) was not up-regulated at the protein level. CONCLUSION: The A(1)R mediates the antilipolytic actions of adenosine. Deletion of the A(1)R in mice does not result in compensatory increases in G-protein-mediated antilipolytic actions of PGE(2) or nicotinic acid.

Cardioprotection by ecto-5'-nucleotidase (CD73) and A2B adenosine receptors.

BACKGROUND: Ecto-5'-nucleotidase (CD73)-dependent adenosine generation has been implicated in tissue protection during acute injury. Once generated, adenosine can activate cell-surface adenosine receptors (A1 AR, A2A AR, A2B AR, A3 AR). In the present study, we define the contribution of adenosine to cardioprotection by ischemic preconditioning. METHODS AND RESULTS: On the basis of observations of CD73 induction by ischemic preconditioning, we found that inhibition or targeted gene deletion of cd73 abolished infarct size-limiting effects. Moreover, 5'-nucleotidase treatment reconstituted cd73-/- mice and attenuated infarct sizes in wild-type mice. Transcriptional profiling of adenosine receptors suggested a contribution of A2B AR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in A1 AR-/-, A2A AR-/-, or A3 AR-/- mice but not in A2B AR-/- mice or in wild-type mice after inhibition of the A2B AR. Moreover, A2B AR agonist treatment significantly reduced infarct sizes after ischemia. CONCLUSIONS: Taken together, pharmacological and genetic evidence demonstrate the importance of CD73-dependent adenosine generation and signaling through A2B AR for cardioprotection by ischemic preconditioning and suggests 5'-nucleotidase or A2B AR agonists as therapy for myocardial ischemia.

Endogenous adenosine inhibits CNS terminal Ca(2+) currents and exocytosis.

Bursts of action potentials (APs) are crucial for the release of neurotransmitters from dense core granules. This has been most definitively shown for neuropeptide release in the hypothalamic neurohypophysial system (HNS). Why such bursts are necessary, however, is not well understood. Thus far, biophysical characterization of channels involved in depolarization-secretion coupling cannot completely explain this phenomenon at HNS terminals, so purinergic feedback mechanisms have been proposed. We have previously shown that ATP, acting via P2X receptors, potentiates release from HNS terminals, but that its metabolite adenosine, via A(1) receptors acting on transient Ca(2+) currents, inhibit neuropeptide secretion. We now show that endogenous adenosine levels are sufficient to cause tonic inhibition of transient Ca(2+) currents and of stimulated exocytosis in HNS terminals. Initial non-detectable adenosine levels in the static bath increased to 2.9 microM after 40 min. These terminals exhibit an inhibition (39%) of their transient inward Ca(2+) current in a static bath when compared to a constant perfusion stream. CPT, an A(1) adenosine receptor antagonist, greatly reduced this tonic inhibition. An ecto-ATPase antagonist, ARL-67156, similarly reduced tonic inhibition, but CPT had no further effect, suggesting that endogenous adenosine is due to breakdown of released ATP. Finally, stimulated capacitance changes were greatly enhanced (600%) by adding CPT to the static bath. Thus, endogenous adenosine functions at terminals in a negative-feedback mechanism and, therefore, could help terminate peptide release by bursts of APs initiated in HNS cell bodies. This could be a general mechanism for controlling transmitter release in these and other CNS terminals.

Role of the influenza virus heterotrimeric RNA polymerase complex in the initiation of replication.

Both transcription and replication of the influenza virus RNA genome are catalysed by a virus-specific RNA polymerase. Recently, an in vitro assay, based on the synthesis of pppApG, for the initiation of replication by recombinant RNA polymerase in the absence of added primer was described. Here, these findings are extended to show that adenosine, AMP and ADP can each substitute for ATP in reactions catalysed by either recombinant ribonucleoprotein or RNA polymerase complexes with either model virion RNA (vRNA) or cRNA promoters. The use of either adenosine or AMP, rather than ATP, provides a convenient, sensitive and easy assay of replication initiation. Moreover, no pppApG was detected when a PB1-PA dimer, rather than the trimeric polymerase, was used to catalyse synthesis, contrasting with a previous report using baculovirus-expressed influenza RNA polymerase. Overall, it is suggested that the heterotrimeric polymerase is essential for the initiation of replication.

Role of adenosine in airway inflammation in an allergic mouse model of asthma.

In the present study, we examined dynamic changes in cellular profile of bronchoalveolar lavage (BAL) fluid after adenosine challenge in ragweed sensitized and challenged mice. Mice systemically sensitized and airway challenged with ragweed showed marked airway inflammation manifesting increased eosinophils, lymphocytes, neutrophils and activated macrophages in BAL. Adenosine challenge further enhanced influx of inflammatory cells into BAL, notably neutrophils from 1 to 72 h and eosinophils from 1 to 48 h time-points (p<0.05), which sharply rose at 6-h time-point following adenosine challenge. Greater infiltration of lymphocytes into BAL was observed at 1 and 72 h and macrophages from 6 to 72 h (p<0.05) after adenosine challenge. Accordingly, markers of eosinophils, neutrophils and mast cells were analyzed at 6-h time-point after adenosine challenge. Adenosine challenge significantly increased the levels of eosinophil peroxidase, neutrophil myeloperoxidase and beta-hexosaminidase in BAL. There were more significant effects of adenosine challenge on the degranulation of mast cells in the lung than that in blood. The chemoattractant, eotaxin, was detected in BAL, which increased after adenosine challenge. Theophylline, a non-specific adenosine receptor antagonist, prevented adenosine-enhanced infiltration of inflammatory cells and their respective markers. Our findings suggest that adenosine plays an important role in airway inflammation in an allergic mouse model.

A quartet neural system model orchestrating sleep and wakefulness mechanisms.

Physiological knowledge of the neural mechanisms regulating sleep and wakefulness has been advanced by the recent findings concerning sleep/wakefulness-related preoptic/anterior hypothalamic and perifornical (orexin-containing)/posterior hypothalamic neurons. In this paper, we propose a mathematical model of the mechanisms orchestrating a quartet neural system of sleep and wakefulness composed of the following: 1) sleep-active preoptic/anterior hypothalamic neurons (N-R group); 2) wake-active hypothalamic and brain stem neurons exhibiting the highest rate of discharge during wakefulness and the lowest rate of discharge during paradoxical or rapid eye movement (REM) sleep (WA group); 3) brain stem neurons exhibiting the highest rate of discharge during REM sleep (REM group); and 4) basal forebrain, hypothalamic, and brain stem neurons exhibiting a higher rate of discharge during both wakefulness and REM sleep than during nonrapid eye movement (NREM) sleep (W-R group). The WA neurons have mutual inhibitory couplings with the REM and N-R neurons. The W-R neurons have mutual excitatory couplings with the WA and REM neurons. The REM neurons receive unidirectional inhibition from the N-R neurons. In addition, the N-R neurons are activated by two types of sleep-promoting substances (SPS), which play different roles in the homeostatic regulation of sleep and wakefulness. The model well reproduces the actual sleep and wakefulness patterns of rats in addition to the sleep-related neuronal activities across state transitions. In addition, human sleep-wakefulness rhythms can be simulated by manipulating only a few model parameters: inhibitions from the N-R neurons to the REM and WA neurons are enhanced, and circadian regulation of the N-R and WA neurons is exaggerated. Our model could provide a novel framework for the quantitative understanding of the mechanisms regulating sleep and wakefulness.

Regulation of VEGF and bFGF mRNA expression and other proliferative compounds in skeletal muscle cells.

The role of muscle contraction, prostanoids, nitric oxide and adenosine in the regulation of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endothelial cell proliferative compounds in skeletal muscle cell cultures was examined. VEGF and bFGF mRNA, protein release as well as the proliferative effect of extracellular medium was determined in non-stimulated and electro-stimulated rat and human skeletal muscle cells. In rat skeletal muscle cells these aspects were also determined after treatment with inhibitors and/or donors of nitric oxide (NO), prostanoids and adenosine. Electro-stimulation caused an elevation in the VEGF and bFGF mRNA levels of rat muscle cells by 33% and 43% (P < 0.05), respectively, and in human muscle cells VEGF mRNA was elevated by 24%. Medium from electro-stimulated human, but not rat muscle cells induced a 126% higher (P < 0.05) endothelial cell proliferation than medium from non-stimulated cells. Cyclooxygenase inhibition of rat muscle cells induced a 172% increase (P < 0.05) in VEGF mRNA and a 104% increase in the basal VEGF release. Treatment with the NO donor SNAP (0.5 microM) decreased (P < 0.05) VEGF and bFGF mRNA by 42 and 38%, respectively. Medium from SNAP treated muscle cells induced a 45% lower (P < 0.05) proliferation of endothelial cells than control medium. Adenosine enhanced the basal VEGF release from muscle cells by 75% compared to control. The present data demonstrate that contractile activity, NO, adenosine and products of cyclooxygenase regulate the expression of VEGF and bFGF mRNA in skeletal muscle cells and that contractile activity and NO regulate endothelial cell proliferative compounds in muscle extracellular fluid.

[Functional organization of a photoperiodic brain system]. / Funktsional'naia organizatsiia fotoperiodicheskoi sistemy golovnogo mozga.

The neurofunctional system, which receives a photoperiod, is a photoperiodic brain system. As a part of chronoperiodic system of organism it is involved in perception and transfer of information about the main external Zeitgeber to the peripheral tissues. Such role of photoperiodic system allows it not only synchronize the chronorhythms of different somatic and visceral functions, but also realize the coordination and the modulation of adaptation mechanisms to the stressors influence. The present review is focused on the ways of conduction of photoperiodic information, role of suprachiasmatic nuclei of hypothalamus in endogenous oscillation of chronorhythms and pineal gland as a neuroendocrinal transducer; and also on characteristics of circadian and circannual parts of photoperiodic system. Special attention is given to vegetative part of photoperiodic system and melatonin--"the hormone of dark". It is supposed that adenosine, one of the humoral elements of photoperiodic system, is involved in transfer of duration of the light part of photoperiod. Due to presented data we have come to the conclusion that septohippocampal system is one of the center for saving photoperiodic information.

[Pharmacological study on the effects of the adenosine uptake inhibitor KF24345 on inflammatory diseases].

Adenosine protects against cellular damage and dysfunction under several adverse conditions, including inflammation. We examined the effects of KF24345, a novel adenosine uptake inhibitor, on inflammatory diseases to investigate whether the adenosine uptake inhibition is useful for the treatment of inflammation. KF24345 inhibited adenosine uptake into washed erythrocytes (in vitro) and sampled blood cells from mice after its oral administration (in vivo). KF24345 significantly suppressed lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia in mice, and the effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. In the experimental glomerulonephritis induced in mice by anti-glomerular basement membrane antiserum, KF24345 significantly inhibited proteinuria and glomerular damage without exhibiting the side effects observed following the treatment with prednisolone and cyclophosphamide. In addition, KF24345 ameliorated the severity of experimental acute pancreatitis induced by cerulein or choline-deficient and ethionine-supplemented diet in mice, and it decreased mortality accompanying severe acute pancreatitis. The anti-pancreatitis effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. These results suggest that KF24345 and adenosine uptake inhibitors can be a new therapeutic approach for various inflammatory diseases, including glomerulonephritis and acute pancreatitis.

Adenosine up-regulates cyclooxygenase-2 in human granulocytes: impact on the balance of eicosanoid generation.

Polymorphonuclear neutrophils (granulocytes; PMNs) are often the first blood cells to migrate toward inflammatory lesions to perform host defense functions. PMNs respond to specific stimuli by releasing several factors and generate lipid mediators of inflammation from the 5-lipoxygenase and the inducible cyclooxygenase (COX)-2 pathways. In view of adenosine's anti-inflammatory properties and suppressive impact on the 5-lipoxygenase pathway, we addressed in this study the impact of this autacoid on the COX-2 pathway. We observed that adenosine up-regulates the expression of the COX-2 enzyme and mRNA. Production of PGE(2) in response to exogenous arachidonic acid was also increased by adenosine and correlated with COX-2 protein levels. The potentiating effect of adenosine on COX-2 could be mimicked by pharmacological increases of intracellular cAMP levels, involving the latter as a putative second messenger for the up-regulation of COX-2 by adenosine. Specific COX-2 inhibitors were used to confirm the predominant role of the COX-2 isoform in the formation of prostanoids by stimulated PMNs. Withdrawal of extracellular adenosine strikingly emphasized the inhibitory potential of PGE(2) on leukotriene B(4) formation and involved the EP(2) receptor subtype in this process. Thus, adenosine may promote a self-limiting regulatory process through the increase of PGE(2) generation, which may result in the inhibition of PMN functions. This study identifies a new aspect of the anti-inflammatory properties of adenosine in leukocytes, introducing the concept that this autacoid may exert its immunomodulatory activities in part by modifying the balance of lipid mediators generated by PMNs.