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Review Article

Adenosine and receptors: Newer therapeutic perspective S. Manjunath, Pranavkumar M. Sakhare

ABSTRACT

Adenosine, a has been described as a ‘retaliatory metabolite’ by virtue of its ability to function in an autocrine manner and to modify the activity of a range of cell types, following its extracellular accumulation during cell stress or injury. These effects are largely protective and are triggered by binding of adenosine to any of the four adenosine Department of Pharmacology, M.R. subtypes namely A1, A2a, A2b, A3, which have been cloned in humans, and Medical College, Sedam Road, are expressed in most of the organs. Each is encoded by a separate and has different Gulbarga-585 105, India functions, although overlapping. For instance, both A1 and A2a receptors play a role in regulating myocardial oxygen consumption and coronary blood flow. It is a proven fact RReceived:eceived: 10.03.2009 RRevised:evised: 31.03.2009 that adenosine plays pivotal role in different physiological functions, such as induction AAccepted:ccepted: 08.06.2009 of sleep, neuroprotection and protection against oxidative stress. Until now adenosine was used for certain conditions like paroxysmal supraventricular (PSVT) and DDOI:OI: 10.4103/0253-7613.55202 Wolff Parkinson White (WPW) syndrome. Now there is a growing evidence that adenosine CCorrespondenceorrespondence to:to: receptors could be promising therapeutic targets in a wide range of conditions including Dr. S. Manjunath cardiac, pulmonary, immunological and inflammatory disorders. After more than three E-mail: manjunath_pharmacology@ decades of research in medicinal chemistry, a number of selective and antagonists yahoo.com of adenosine receptors have been discovered and some have been clinically evaluated, although none has yet received regulatory approval. So this review focuses mainly on the newer potential role of adenosine and its receptors in different clinical conditions.

KKEYEY WWORDS:ORDS: Anaesthesia and critical care, asthma, epilepsy, inflammatory bowel diseases, ischaemia/reperfusion injury, Parkinson’s disease, refractory primary pulmonary hypertension

Introduction was mainly used for terminating paroxysmal supraventricular tachycardia (PSVT) and Wolff Parkinson White (WPW) syndrome. Adenosine is a metabolite of (ATP), having a very short half-life (1.5 s) due to its rapid metabolism Now, with advances in understanding of adenosine receptors and [Figure 1]. It accumulates in the area where ATP is utilised development of agonists and antagonists [Table 2], adenosine but not reformed, for example during ischaemia and possibly receptors have emerged as potential newer therapeutic targets. during sepsis. Unlike ATP, adenosine exists free in cytosol of all Mainly, A2a receptor plays an important role in mediating [3] cells and is transported in and out of the cell by a membrane inflammatory and immune responses. Its actions through the transporter. It is not a conventional transmitter but a sort of various subtypes, bring about a decrease local hormone or better say ‘homeostatic modulator’. in energy demand and an increase in energy supply and thus Adenosine is an endogenous purine nucleoside that mediates are protective.[4] Similar to endocannabinoid, the neuromodular a wide variety of physiological functions by interacting with four adenosine plays a very important integrative role in striatal cell surface receptors namely A1, A2a, A2b and A3 [Table 1]. function.[5] Adenosine and interactions, Adenosine is an intermediate metabolite in many important also have integrative mechanism in .[6] In addition, biochemical pathways and has been shown to play a role in several drugs act through modulation of adenosine effect like the regulation of coronary and systemic vascular tone, methylxanthine, , ketamine, beta blockers, function and lipolysis in adipocytes.[1,2] In addition, it mediates channel blockers, dopamine, cannabinoids etc. Adenosine important functions like induction of sleep, antioxidant and, also plays an important role in renal function. Renal tubular antiseizure effects, neuroprotection etc. Until now adenosine sodium transport is the principal consumer of ATP.[7] Sodium

Indian J Pharmacol | Jun 2009 | Vol 41 | Issue 3 | 97-105 97 Manjunath and Sakhare: Adenosine: Newer therapeutic perspective

Table 1 Figure 1: Metabolism of adenosine. ATP, adenosine triphosphate; ADP, ; AMP, . Modulating Adenosine receptor – Mediated effects in various organ systems various /transporters will increase endogenous adenosine concentrations Receptor Effects on Stimulating the Receptors subtypes

A1 Cardiovascular • Slows AV nodal conduction (negative dromotropy) ATP ADP AMP • ↓ (negative chronotropy) Adenosine kinase 5’ Nucleotidase • ↓ atrial contractility (negative inotropy) Adenosine • ↓ β-adrenergic tone (AMP or Adenosine diffuse extracellularly) • Inhibits pacemaker and L-type calcium currents Nucleoside Nucleoside Transport Renal inhibits transport (Moves adenosine into endothelial cells) • Inhibits release of renin inhibitors • ↑ reabsorption of sodium in proximal convoluted tubule e.g. R75231 Adenosine Deaminase • Vasoconstriction of afferent arteriole - ↓ GFR CNS Ischemia • ↓ neurotransmitter release • Sedation oxidase Xanthine dehydrogenase • Anticonvulsant effects Xanthine + Superoxide anions Metabolic • Inhibits lipolysis • ↑ insulin sensitivity There is a growing interest in elucidating the mechanisms A2a Cardiovascular by which adenosine inhibits . Hence, these • Coronary and peripheral inhibitory adenosine receptors (Gi-A1 and A3) and their • Inhibits platelet aggregation downstream signaling pathways are promising targets for A2b Pulmonary newer antiinflammatory therapies. By signalling through the

• Vasodilation A2a adenosine receptors, adenosine suppresses the release of [3] • Mast cell release of IL-8 → Potential bronchoconstriction inflammatory mediators, primarily by inhibiting lymphoid or and inß ammation myeloid cells including neutrophils, macrophages, lymphocytes,

A3 Pulmonary and . • Mast cell release of allergic mediators → Potential Newer potential therapeutic role of adenosine and its bronchoconstriction receptors AV indicates atrioventricular, GFR, glomerular Þ ltration rate: IL interleukin Bronchial asthma: Adenosine, a primordial signalling molecule, produces a number of physiological and pathophysiological effects in the human body. It has been transport is influenced by changes in glomerular filtration rate shown that stable form of adenosine, i.e. the (GFR) and by primary changes in tubular transport. Intrarenal adenosine monophosphate (AMP) induces bronchoconstriction adenosine released by cleavage of ATP, maintains the balance in asthma, but not in normal airways. Following facts convince between energy supply and demand by affecting both of these that adenosine plays a key role in pathophysiology of asthma and processes. In the renal microcirculation, adenosine receptors has an important function in acute bronchoconstrictor [Figure exert control over renal blood flow, GFR, renin release and 2] and airway inflammatory responses in humans. tubuloglomerular feedback.[8] • Adenosine levels are increased in broncho-alveolar-

Table 2

Comparison of subtypes

Adenosine receptors

Receptor Gene Mechanism Agonists Antagonists

A1 ADORA1 Gi/o --> cAMP↓ N6-Cyclopentyladenosine , , 8-Cyclopentyl-1, Inhibition ↓ vesicle release, CCPA, 2’-MeCCPA 3-dimethylxanthine (CPX), ↓ NMDA receptor activity GR 79236, SDZ WAG 994 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), 8-Phenyl 1,3-dipropylxanthine, PSB 36

A2a ADORA2A Gs --> cAMP↑ ATL-146e, CGS-21680, Caffeine, theophylline, , SCH-58261, SCH-442,416 ZM-241,385

A2b ADORA2B Gs --> cAMP↑ 5’-N ethylcarboxamidoadenos ne, Theophylline, CVT-6883, MRS-1706, MRS- BAY 60–6583, LUF-5835, LUF-5845. 1754, PSB-603, PSB-0788, PSB-1115

A3 ADORA3 Gi/o --> cAMP↓ 2-(1-Hexynyl)-N methyl adenosine, Theophylline, MRS-1191, MRS-1220, MRS- CF-101 (IB-MECA), 2-Cl-IB-MECA, 1334, MRS-1523, MRS-3777, MRE3008F20, CP-532,903; MRS-3558 PSB-10, PSB-11, VUF-5574

98 Indian J Pharmacol | Jun 2009 | Vol 41 | Issue 3 | 97-105 Manjunath and Sakhare: Adenosine: Newer therapeutic perspective

Figure 2: Schematic diagram of the mechanism involved in adenosine-induced bronchoconstriction. Once generated, adenosine

activates the adenosine A2b receptors on mast cells. Upon activation of A2b receptors, various inß ammatory mediators that induce bronchoconstriction are released. ADP = adenosine diphosphate: AMP = adenosine monophosphate; ATP = adenosine triphosphate; NT = nucleotidase; NTPD= nucleoside triphosphate diphosphohydrolase. Mast cell

ATP ADP NTPDase AMP

ATP Adenosine Ecto kinase 5’NTase

AR2b Adenosine Adenosine Adenosine Nucleoside (AMP) deaminase transporter Prostanoids,

Cytokines leukotriene C4 lonosine Histamine Sensory C fibre nerve

Bronchoconstriction Adenosine-producing cell

Smooth muscle cells

lavage fluid[9] and exhaled breath condensate of patients a serious disease in which the pulmonary vascular resistance with allergic asthma[10] and in the plasma of patients with remains elevated during the neonatal period. It is a clinical exercise-induced asthma.[11] syndrome that may occur in association with diverse neonatal • The sensitivity of airways to adenosine and adenosine cardiorespiratory disorders, such as meconium aspiration, monophosphate (AMP), which is metabolized locally by sepsis, pneumonia, acute respiratory distress syndrome, the 5’ nucleotidase to adenosine, more closely reflects asphyxia, congenital diaphragmatic hernia or lung hypoplasia. an inflammatory process and the phenotype for allergic As a matter of fact, it is often difficult to rapidly make the asthma. [12,13] correct diagnosis since it may share common pathophysiologic • Adenosine induces hyperresponsiveness in the airways of and clinical features with other diseases. Primary pulmonary asthmatics, in vivo following inhalation and in vitro in small hypertension of the newborn contributes to neonatal hypoxemia, airways.[14,15] which is often refractory and remains a major clinical problem, • At therapeutic plasma levels, less than those required to significantly contributing to morbidity and mortality in term and inhibit phospho-diesterase both theophylline, a non- preterm neonates. Indeed, this condition is traditionally treated selective adenosine and bamiphylline, by correcting the primary and triggering factors, whenever a selective A1 adenosine receptor antagonist (which does possible and by using conventional protocols including recent

not bind to human A2b and A3 receptors), improve lung ventilation strategies (high-frequency oscillatory ventilation), function and symptoms in humans with asthma.[16,17] maintenance of a reasonable electrolytic and acid-base balance, • Adenosine elicits hyperreactive airway response in humans nutritional support and the use of non-specific agents like alkali with allergic asthma by acting on its receptors. All the infusion, sulphate, prostacyclin, tolazoline and more four adenosine receptors, which have been cloned in specific pulmonary vasodilator agents like nitric oxide.[19,20] humans, are expressed in lung and all are targets for drug Recent reports recommend the use of adenosine infusion for development for human asthma.[18] PPHN, alone or associated with other strategies, for refractory scenarios. The pathophysiologic hypothesis is supported by Refractory primary pulmonary hypertension (RPPH) the fact that pulmonary vasodilation is achieved by two known Primary pulmonary hypertension of the newborn (PPHN) is pathways. Nitric oxide acts by elevating intracellular cyclic

Indian J Pharmacol | Jun 2009 | Vol 41 | Issue 3 | 97-105 99 Manjunath and Sakhare: Adenosine: Newer therapeutic perspective monophosphate levels resulting in smooth muscle this receptor subtype and their testing in models of intestinal relaxation with a specific potent vasodilator effect.[21] On the inflammation. In a study by Odashima et al.,[24] the potential other hand, adenosine causes potent selective pulmonary antiinflammatory effect of ATL-146e, a selective A2a receptor vasodilation by acting at adenosine receptors (A2) on vascular , was investigated on the acute and chronic model smooth muscle to increase intracellular cyclic adenosine 3’5’ of colitis evoked by formalin-immune complex in rabbits, monophosphate (AMP),[22] resulting in smooth muscle relaxation as well as in a model of spontaneous ileitis in SAMP1/YitFc and improvement in systemic and myocardial oxygen delivery. mice. The stimulation of A2a receptors was associated with Adenosine may also stimulate K+ ATP channels, resulting in a significant amelioration of inflammation in the intestinal hyperpolarization of smooth muscle. The rationale behind mucosa, with a reduction of leucocyte infiltration and inhibition its use is more consistent with the fact that patients with of proinflammatory cytokine levels (TNF-α, IFN-γ and IL-4). pulmonary hypertension have low adenosine levels. However, it has been recently observed that the selective A2a Inflammatory bowel diseases (IBDs): Traditional medical receptor agonist CGS21680 was ineffective in ameliorating treatments for inflammatory bowel diseases have focused on various inflammatory parameters of colitis induced by dextran nonspecific suppression of immune reaction and inflammation sodium sulphate (DSS) in mice. Overall, the actual significance of with limited efficacy and safety. However, recent advances in A2a receptors in the pathophysiology of intestinal inflammation the knowledge of enteric immunopathogenesis have paved the remains undetermined, and further investigations are required way to targeted therapies, allowing a selective blockade of to establish the therapeutic relevance of A2a agonists in the inflammatory cascade and modulation of key cytokines. In IBD. Adenosine A3 receptors are also emerging as possible the search for novel therapeutic options, increasing attention targets for treatment of bowel inflammation.[25] IB-MECA, an is being paid to the adenosine system and its involvement A3 receptor agonist, exerted significant ameliorative effects, in the pathophysiology of IBDs. The potential therapeutic both in DSS-induced intestinal inflammation and spontaneous applications resulting from its pharmacological modulation colitis in IL-10 deficient mice. In particular, this drug markedly have been recognized in recent years. The expression of reduced the colonic levels of the proinflammatory cytokines IL- adenosine receptor subtypes in the gastrointestinal tract has 1, IL-6 and IL-12 and decreased the local production of MIP-1α been investigated in humans and evidence has been obtained (Macrophage Inflammatory -1alpha), and MIP-2, with a for their localization, both in small and large bowel. powerful downregulation of leucocyte trafficking in both models Once released at sites of inflammation, adenosine plays of bowel inflammation. Treatment with IB-MECA prevented the prominent roles in maintaining tissue integrity by modulation induction of various cytokine/chemokine/inflammatory , of immune functions, down-regulation of phlogistic reactions, together with a marked suppression of ROS (Reactive Oxygen interference with the biosynthesis of proinflammatory cytokines Species) production and a significant amelioration of intestinal and inhibition of neutrophil adhesion, degranulation and anti- damage. As an alternative strategy to the direct pharmacological oxidant activity.[23] In these settings, the concentrations of modulation of adenosine receptors, it has been proposed that adenosine closely reflect the metabolic status of the tissue, the elevation of endogenous adenosine concentrations, through and it has been proposed that the purinergic system may act the blockade of pivotal catabolic enzymes, might exert a as a sensor apparatus, which provides the immune system with beneficial influence on enteric inflammation. Various authors essential information about tissue health, thus contributing have reported a significant increase in adenosine-deaminase to the resolution of inflammation. In gastrointestinal expression and activity in inflamed tissues, including intestinal tract, adenosine also contributes to the control of enteric ones and the association of a defective adenosine production, neurotransmission and smooth muscle contractility, thus with chronicization of the phlogistic conditions.[26] In a model of participating in physiological regulation of gut motor functions. experimental colitis induced by dinitrobenzene sulphonic acid Under physiological conditions, adenosine is mainly formed at (DNBS), the results indicated that the blockade of adenosine the intracellular level from S-adenosylhomocysteine hydrolase. conversion into inosine, promoted by inhibition of adenosine However, in the presence of adverse situations such as deaminase, was able to protect the colonic tissues from hypoxia or inflammation, adenosine production occurs both inflammatory injury. This effect was associated with a significant intracellularly and extracellularly by dephosphorylation of ATP reduction of TNF-α release, neutrophil infiltration and ROS via 5’-nucleotidase enzymes accompanied by suppression of production.[27] Cellular adenosine uptake is another key event adenosine kinase activity [Figure 3]. regulating extracellular adenosine concentrations, and therefore As discussed above, adenosine can exert antiinflammatory the inhibition of nucleoside transporters could represent a actions in a variety of systems, including the gastrointestinal further approach to enhance the antiinflammatory actions of tract. The involvement of the adenosine system in the this nucleoside. In this regard, a recent in vitro study compared antiinflammatory action has been recognized since the early the immunomodulatory effects of dipyridamole (a non-selective 1990s. In recent years, increasing interest is being focused inhibitor of adenosine uptake) with that of , on the search for drugs that act via a direct stimulation of evaluating the effects of these drugs on TNF-α and IL-10 adenosine receptor subtypes, in particular A2a and A3 or release from intestinal mononuclear cells obtained either from through an increase in local adenosine concentration and could patients with Crohn’s disease or healthy controls and stimulated offer novel therapeutic options for treatment of IBDs. The large with LPS (lipopolysaccharide) and phytohemagglutinin. The body of evidence supporting the prominent role played by A2a results showed a significant suppression of TNF-α levels in receptors in the antiinflammatory actions of adenosine has cells treated with both drugs whereas dipyridamole was more prompted the synthesis of drugs acting as selective agonists of effective than methotrexate in increasing IL-10 levels.[28] Thus

100 Indian J Pharmacol | Jun 2009 | Vol 41 | Issue 3 | 97-105 Manjunath and Sakhare: Adenosine: Newer therapeutic perspective

Figure 3: Biosynthesis and catabolism of adenosine under normal conditions (A) or in the presence of inß ammation (B). Endo-ADA: endo-adenosine deaminase; Ecto-ADA: ecto-adenosine deaminase; ATP: adenosine triphosphate; ADP: adenosine diphosphate; AMP: adenosine monophosphate; AK: adenosine kinase; SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine; CD73/Ecto-5-N: ecto-5-nucleotidase; Endo-5-N: endo-5-nucleotidase; NT: .

with development of these adenosine receptor modulators, new contraction, vasodilatation, signal transduction and secretion door for the treatment of IBD has opened. in a variety of cell types.[29] Recently established and potential Anaesthesia and intensive care medicine: Extracellular clinical applications of adenosine, ATP in general and ATP– adenosine and adenosine triphosphate (ATP) are involved in MgCl2 in intensive care medicine have been well documented. biological processes including neurotransmission, muscle Several double-blind, placebo-controlled, cross-over studies

Indian J Pharmacol | Jun 2009 | Vol 41 | Issue 3 | 97-105 101 Manjunath and Sakhare: Adenosine: Newer therapeutic perspective in healthy human subjects, have shown pain-reducing effects by the activity of its major metabolic enzyme adenosine kinase of intravenous adenosine infusion at doses of 50–70 mg/kg/ (ADK),[41] which in the adult brain is predominantly expressed in min.[30] In addition, the effectiveness of adenosine in reducing astrocytes. Consequently, astrogliosis in epilepsy is associated ischaemic pain (70 mg/kg/min IV for 30 min) is comparable to with upregulation of ADK.[42] Transgenic upregulation of ADK morphine (20 mg/kg/min IV for 5 min) or ketamine (20 mg/kg/ in brain leads to a reduction in the tone of ambient adenosine min IV for 5 min). Furthermore, adenosine given in combination and therefore is associated with increased susceptibility to with morphine or ketamine has an additive effect on pain seizures[43] and ischaemic cell death. These findings provide reduction.[31] A recent study[32] suggested that, adenosine a neurochemical rationale for therapeutic intervention.[44] infusion during general anaesthesia for surgery provided good Consequently, cultured cells engineered to release adenosine recovery from anaesthesia, associated with pronounced and by disrupting their Adk gene were tested as therapeutic brain sustained postoperative pain relief. In this study, adenosine implants in the rat kindling model. These studies have provided (50–500 mg/kg/min), during surgery-induced pain relief, the proof-of-concept that focal augmentation of adenosine by reduced opioid requirements and attenuated side-effects, such cellular brain implants can reduce induced (kindled) seizures as protracted sedation, cardiorespiratory instability, nausea and and the progression of kindled seizure severity.[45] Hence, vomiting, during the postoperative recovery period. Adenosine adenosine kinase inhibitor like GP515 has been discovered. was superior to remifentanil (0.05–0.5 mg/kg/min) in all these However, it remains to be demonstrated whether focal aspects. augmentation of adenosine can prevent the development of These results suggest that adenosine could be very useful spontaneous seizures, i.e. true epileptogenesis. in anaesthesia and intensive care medicine, where it acts by Ischaemia/reperfusion (I/R) Injury: Ischaemic inhibiting nociceptive transmission. preconditioning (IPC) refers to the mechanism whereby brief Epilepsy: Current therapies of epilepsy largely rely on the periods of ischaemia/reperfusion render a tissue relatively suppression of spontaneous seizures by pharmacotherapy or resistant to the harmful effects of subsequent prolonged periods surgical intervention; however, till date no effective prophylaxis of ischaemia/reperfusion. First described in canine hearts or true pharmacotherapeutic cure is available. Epileptogenesis in 1986, IPC has been shown to occur in most species and i.e. the process that leads to epilepsy and spontaneous seizures tissues. [46] The exact mechanism of IPC may vary in different is thought to be triggered by an initial acute brain injury, e.g. tissues and species where adenosine has an important role.[47-49] status epilepticus, followed by progressive neuronal cell loss, This ‘adenosine theory’ is supported by three facts: mossy fibre sprouting and formation of an astrogliotic scar. [33] • Interstitial adenosine concentration doubles after 5 min of However, it is presently unclear why some brain injuries cardiac ischaemia.[50] evolve into epilepsy while others do not. Therefore, the • Adenosine antagonists reduce the effect of cardiac IPC.[47,48] identification of diagnostic markers to predict epileptogenesis • Adenoreceptor stimulation reduces myocardial is of utmost importance. The identification of astrogliosis damage following ischaemia/reperfusion[51] and during as a hallmark in brain of epileptics, and the identification of cardiopulmonary bypass.[52] astrocytes as important modulators of neuronal activity imply Adenosine may attenuate ischaemia/reperfusion injury by a that dysfunction of astrocytes might play a key role in the number of possible mechanisms,[53] including purine salvaging, pathogenesis of epilepsy.[34] Animal models of epileptogenesis improved tissue perfusion, antiinflammatory action and a direct have been developed that closely mimic the pathogenesis intracellular initiator/effector mechanism. of human mesial temporal lobe epilepsy, a form of human Purine salvaging: In this process, adenosine acts as a focal epilepsy that is frequently associated with progression substrate for ATP production. This appears unlikely, as studies to chronic intractable epilepsy. These models rely on the have failed to show an improvement in the replenishment of intrahippocampal,[35] intraamygdaloid or intracerebroventricular the nucleotide pool.[54] administration of small doses of kainic acid (KA). As a primary Improved tissue perfusion: Administration of high doses of consequence of KA injection, status epilepticus is elicited, which adenosine have shown to increase tissue perfusion.[55] Adenosine in turn leads to a characteristic pattern of hippocampal cell infusion significantly reduces capillary hyperpermeability, death, mossy fibre sprouting, astrogliosis and spontaneous leucocyte adherence and leucocyte extravasation.[56] recurrent seizures[35] during a span of several weeks. Antiinflammatory action: Certain in vitro experiments Adenosine is an inhibitory modulator of brain activity. By on ischaemia/reperfusion[55] have demonstrated a maximum acting on its receptors, mainly by activation of A1 receptors in reduction in granulocyte respiratory burst activity of 20%, using hippocampus, it exerts predominant inhibitory effects.[36] These an adenosine concentration of 1 µM. However, the remaining 80% inhibitory actions of adenosine can be used therapeutically of activity (37 nmol O2/min per million neutrophils) is toxic to to suppress seizures[37] and are considered important for cultured endothelial cells.[57] It was concluded that the protective maintaining postictal depression[38] and for restoring the effect observed in the in vivo study was due to the 65% decrease metabolic equilibrium following seizures.[39] However, despite in leucocyte extravasation during reperfusion, rather than due to more than 20 years of research on the role of adenosine in a 20% reduction in respiratory burst activity. [55] experimentally induced seizures and the identification of Direct intracellular initiator/effector mechanism: A direct adenosine as endogenous anticonvulsant of the brain,[40] the intracellular effect of IPC[53] has been proposed to include all pathogenic role of the adenosine system in epileptogenesis of the preceding observations, while explaining the role of remains understudied. other mediators and the delayed (days or weeks) protective Ambient concentrations of adenosine are largely regulated effect of IPC.

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By all the above-mentioned mechanisms, adenosine could rationale for their development as anti-Parkinsonian agents. be very useful in handling the ischaemia/reperfusion injury. Relatively specific A2a receptor antagonists consistently Sepsis: Thiel and colleagues[58] investigated pretreatment of reverse motor deficits or enhance dopaminergic treatments porcine endotoxaemia (Salmonella abortus equi endotoxin 5 µg/ in animal models of PD. For example, in rats with unilateral kg/h IV injection) with adenosine (150mg/kg/hr intravenous 6-hydroxydopamine (6-OHDA) lesions of the dopaminergic injection started before endotoxin infusion). Adenosine had no pathway, A2a receptor antagonists including KF17837, KW- effect on endotoxin-induced neutropenia, neutrophil binding/ 6002 and MSX-3 potentiated the contralateral turning behaviour phagocytosis of complement-opsonized zymosan or luminal- induced by levodopa or a dopamine agonist.[62] In addition, enhanced neutrophil chemiluminescence, in response to motor stimulation by an A2a receptor antagonist in this model complement-opsonized zymosan. It did, however, strongly showed no tolerance after repeated treatment. Furthermore, inhibit extracellular superoxide anion release, as measured by the case for developing antagonists as lucigenin-enhanced neutrophil chemiluminescence, in response anti-Parkinsonian therapy has been built on a solid foundation to complement-opsonized zymosan. of preclinical evidence.[63] Following a soft tissue injury and the induction of As hypolipidaemic agent: Coronary artery disease (CAD) hemorrhagic shock,[59] mongrel pigs were resuscitated with is the leading cause of death in the industrialized nations, Ringer lactate solution (control) or Ringer lactate solution plus accounting for 42% of all deaths and for 50% of the total acadesine, an adenosine precursor in the dose of (1 or 10 mg cardiovascular healthcare expenditure.[64] Despite efforts to bolus intravenously every 12 h, with an initial IV injection treat dyslipidaemia with proper diet and drug treatment, CAD of 0.5 mg/kg/min for 30 min). Seventy-two hours later, the remains one of the most common cause of death. Many risk animals received Escherichia coli 0111:B4 endotoxin (0.5 µg/ factors (e.g., older age, male gender, hypertension, diabetes, kg over 30 min). The higher dose acadesine treatment had the smoking, etc.) are associated with the development and following effects: progression of CAD and among them are the serum lipid • Reduced the endotoxin-induced increase in alveolar protein abnormalities or dyslipidaemias. High total and low density extravasation, systemic oxygen consumption and cardiac lipoprotein (LDL) cholesterol levels are strongly related to index. CAD risk, and reductions in LDL levels are associated with • Reduced the endotoxin-induced hypoxia and early transient reduced coronary disease risk. The importance of elevated pulmonary hypertension. triglycerides (TGs) as an independent risk factor of CAD has • Reduced the fluid requirement necessary to maintain been controversial. Recently, a metaanalysis of 17 prospective systemic hemodynamics. studies of TG levels and cardiovascular disease showed that • Reduced mortality and prolonged survival time. elevated TG levels can be an independent risk factor for CAD.[65] It had no effect on endotoxin-induced leucopoenia or RPR749 (molecular formula C22H26F3N7O3, molecular tumour-necrosis factor production. In this study, acadesine weight 493.49) is a potent and selective adenosine A1 agonist may have been acting as an adenosine precursor but also could targeted for the management of hypertriglyceridaemia[66] have been acting as a free radical scavenger,[60] which can be a to reduce/normalize TG levels, leading to a reduction in potential therapeutic tool for treatment of sepsis. death and morbidity from CAD with little effect on other Parkinson’s disease: Although current medication receptors. The methylated metabolite of RPR749 shows treatment of Parkinson’s disease (PD) provides good benefit for similar pharmacological properties. In the animal models of number of years, long-term treatment remains inadequate. The hypertriglyceridaemia, RPR749 also appears to lower free underlying neuronal degeneration continues to progress and fatty acid (FFA) and insulin levels and may have additional many patients develop long-term complications of the dopamine lipid-modifying effects. replacement therapy. Continued neuronal degeneration can lead As stated above there is a clear need for developing drugs to the emergence of dementia or imbalance, problems that can that can reduce TG levels. The current therapy includes statins, cause substantial disability and that are poorly responsive to fibrates and niacinic acid. Fibrates (gemfibrozil, fenofibrate symptomatic treatment. and bezafibrate) reduce TGs by approximately 35% and lower Due to these limitations of current therapy, an intense search LDL at doses of approximately 600 mg/d administered twice for new medications to treat PD is ongoing. There is a need daily, but are associated with gallstones and gastrointestinal for medications that can slow the underlying progression of disorders. Nicotinic acid can also lower TGs by approximately degeneration, improve PD symptoms in early disease without 35% and decrease LDL at doses of 3 g/d given three times daily inducing dyskinesia and improve motor fluctuations and ‘off’ but is associated with an extremely poor side effect profile and time in advanced disease without worsening dyskinesia. Much is contraindicated in patients with diabetes. Statins (lovastatin, interest has focused on non-dopaminergic therapies, especially pravastatin, simvastatin, atorvastatin and cerivastatin) at dose adenosine A2a receptor antagonists. Istradefylline (KW-6002) of 20–80 mg/d lower TG levels by approximately 25% and can is an adenosine A2a receptor antagonist that is now in phase decrease LDL but may be associated with myopathy. The target III clinical trials for PD.[61] was to achieve at least 35% or more lowering of TG levels by Although the anatomy of the A2a receptor distinguishes it RPR749 based on the efficacy of other available therapies. from other non-dopaminergic targets in the quest for improved RPR749 (0.1–30 mg/kg) has been shown to reduce TG levels anti-Parkinsonian therapy, it is the behavioural pharmacology from 20 to 70%[67] and thus could be important tool in treating of A2a receptor antagonists that has provided the central coronary artery disease.

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Conclusions 15. Bjorck T, Gustafsson LE, Dahlen SE. Isolated bronchi from asthamtics are hyper- responsive to adenosine, which apparently act indirectly by liberation of Adenosine is very useful therapeutic tool in handling a leutotrienes and histamine. Am Rev Respir Dis 1992;145:1087-91. variety of clinical conditions like ischaemia/reperfusion injury 16. Catena E, Gunella G, Monici PPA, Oliani C.Evaluation of the risk / beneÞ t ratio and refractory primary pulmonary hypertension. In addition, it of bamiphylline in the treatment of chronic obstructive lung disease. Italian J has created its own place in the field of anaesthesia and critical Chest Dis 1988;42:419-26. 17. Crescioli S, Spinazzi A, Plebani M, Pozzani M, Mapp CE, Boschetto P, et al. medicine. Alternatives to adenosine administration include Theophylline inhibits early and late asthmatic reactions induced by allergens in modulation of its metabolism and administration of specific asthmatic subjects. 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