Neuroprotection induced by the adenosine A<Subscript>2A</Subscript> antagonist CSC in the 6-OHDA rat model of parkinsonism: effect on the activity of striatal output pathways

In Parkinsons disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A_2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A_2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A_2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A_2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved.     

Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis

Fibrocytes are circulating mesenchymal precursors (CD45+, col 1+) recruited to fibrotic areas. Fibrocytes secrete profibrotic mediators including periostin; a matricellular protein that regulates cellular interactions with extracellular matrix (ECM) components. In bleomycin-induced fibrosis, periostin deficiency in structural or hematopoietic cells limits development of pulmonary fibrosis. To determine if hematopoietic-derived fibrocytes might secrete soluble factors to activate structural myofibroblast differentiation, wild-type (WT) fibroblasts were treated with conditioned medium from fibrocytes isolated from bleomycin-treated WT or periostin^−/− mice. After 24 h we saw less α-smooth muscle actin expression in cells treated with conditioned medium from periostin^−/− fibrocytes. Adoptive transfer of WT fibrocytes augmented lung fibrosis to a greater extent than transfer of fibrocytes from periostin^−/− mice. In vitro analysis of fibrocytes and fibroblasts isolated from WT and periostin^−/− mice treated with TGFβ1 or periostin demonstrated co-regulation of mesenchymal activation and beta 1 integrin as a potential receptor for periostin on fibrocytes. Additionally, connective tissue growth factor (CTGF) mRNA expression was increased in fibrocytes treated with periostin whereas CTGF and lysl oxidase (LOX) mRNA expression was low in bleomycin-treated periostin^−/− fibrocytes. These data suggest fibrocytes may augment bleomycin-induced fibrosis via secretion of periostin and other soluble factors that promote myofibroblast differentiation.     

Extracellular Generation of Adenosine by the Ectonucleotidases CD39 and CD73 Promotes Dermal Fibrosis

Adenosine has an important role in inflammation and tissue remodeling and promotes dermal fibrosis by adenosine receptor (A_2AR) activation. Adenosine may be formed intracellularly from adenine nucleotides or extracellularly through sequential phosphohydrolysis of released ATP by nucleoside triphosphate diphosphohydrolase (CD39) and ecto-5′-nucleotidase (CD73). Because the role of these ecto-enzymes in fibrosis appears to be tissue specific, we determined whether these ectonucleotidases were directly involved in diffuse dermal fibrosis. Wild-type and mice globally deficient in CD39 knockout (CD39KO), CD73 (CD73KO), or both (CD39/CD73DKO) were challenged with bleomycin. Extracellular adenosine levels and dermal fibrosis were quantitated. Adenosine release from skin cultured ex vivo was increased in wild-type mice after bleomycin treatment but remained low in skin from CD39KO, CD73KO, or CD39/CD73DKO bleomycin-treated mice. Deletion of CD39 and/or CD73 decreased the collagen content, and prevented skin thickening and tensile strength increase after bleomycin challenge. Decreased dermal fibrotic features were associated with reduced expression of the profibrotic mediators, transforming growth factor-β1 and connective tissue growth factor, and diminished myofibroblast population in CD39- and/or CD73-deficient mice. Our work supports the hypothesis that extracellular adenosine, generated in tandem by ecto-enzymes CD39 and CD73, promotes dermal fibrogenesis. We suggest that biochemical or biological inhibitors of CD39 and/or CD73 may hold promise in the treatment of dermal fibrosis in diseases such as scleroderma.Tissue damage leads to the release of the signaling nucleoside adenosine, which, by engaging specific adenosine receptors (A₁R, A_2AR, A_2BR, and A₃R), exhibits both tissue-protective and tissue-destructive effects.^{1, 2, 3, 4} In particular, adenosine is a potent regulator of tissue repair, and we have previously reported that adenosine promotes dermal fibrosis via the A_2AR receptor, as shown in vitro,⁵ in a bleomycin-induced dermal injury model of scleroderma,⁶ and in a model of elevated tissue adenosine.⁷ Similarly, we found that pharmacological blockade of A_2AR diminishes skin scarring.⁸Elevations in extracellular adenosine can result from either an increase in intracellular adenosine, followed by release into the extracellular space, or the release of adenine nucleotides, followed by their extracellular catabolism into adenosine.⁹ The main source of extracellular adenosine stems from the enzymatic phosphohydrolysis of precursor nucleotides to adenosine.^{10, 11, 12, 13} This is achieved by a two-step enzymatic process involving the ecto-apyrase, CD39 (conversion of ATP/ADP to AMP) and the ecto-5′-nucleotidase, CD73 (conversion of AMP to adenosine).¹⁴ It is widely accepted that CD39 and CD73 promote anti-inflammatory effects of adenosine in the immune system,^{15, 16, 17} and both enzymes have been previously shown to attenuate acute injury and inflammation in models of ambient hypoxia,^{18, 19} cyclic mechanical stretch,²⁰ and bleomycin-induced lung injury.² However, CD39 and CD73 promote fibrosis in murine models of pancreatitis²¹ and hepatic fibrosis,²² respectively, suggesting an important role for CD39 and CD73 in the regulation of fibrogenesis in vivo.We hypothesized that limiting extracellular adenosine levels by CD39 and/or CD73 gene deletion may protect against bleomycin-induced dermal fibrosis, a model of scleroderma. CD39-deficient, CD73-deficient, and CD39/73 double-deficient mice were subjected to bleomycin-induced skin injury, and the extent of skin fibrosis was compared with the wild-type (WT) mice. Our results show that, after bleomycin injection, mice globally null for CD39 and/or CD79 released lower levels of adenosine and concurrently developed less dermal fibrosis, indicating that adenosine generation by CD39 and CD73 is highly likely to be a critical regulator of fibrogenesis in skin.     

Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model of elevated tissue adenosine

Adenosine is a potent modulator of inflammation and tissue repair. We have recently reported that activation of adenosine A(2A) receptors promotes collagen synthesis by human dermal fibroblasts and that blockade or deletion of this receptor in mice protects against bleomycin-induced dermal fibrosis, a murine model of scleroderma. Adenosine deaminase (ADA) is the principal catabolic enzyme for adenosine in vivo, and its deficiency leads to the spontaneous development of pulmonary fibrosis in mice. The aim of this study was to characterize further the contributions of endogenous adenosine and adenosine A(2A) receptors to skin fibrosis. Taking advantage of genetically modified ADA-deficient mice, we herein report a direct fibrogenic effect of adenosine on the skin, in which increased collagen deposition is accompanied by increased levels of key mediators of fibrosis, including transforming growth factor beta1, connective tissue growth factor, and interleukin-13. Pharmacological treatment of ADA-deficient mice with the A(2A) receptor antagonist ZM-241385 prevented the development of dermal fibrosis in this model of elevated tissue adenosine, by reducing dermal collagen content and expression of profibrotic cytokines and growth factors. These data confirm a fibrogenic role for adenosine in the skin and reveal A(2A) receptor antagonists as novel therapeutic agents for the modulation of dermal fibrotic disorders.     

Involvement of brain serotonin 5-HT<Subscript>1A</Subscript> receptors in genetic predisposition to aggressive behavior

Experiments were performed on Norwegian rats selected over more than 59 generations for high and low levels of high-affective defensive aggressivity and on highly aggressive (offensive) Tg8 mice with irreversible monoamine oxidase A knockout. There were significant differences in the functional state and expression of 5-HT_1A receptors between highly aggressive and non-aggressive animals. Functional activity assessed in terms of hypothermia evoked by a 5-HT_1A agonist was significantly greater in non-aggressive rats and mice than in aggressive animals. The high level of functional activity in non-aggressive rats coincided with a greater level of expression of 5-HT_1A receptors in the midbrain. The level of 5-HT^1A receptor mRNA in aggressive mice was unchanged in the midbrain and hypothalamus and was increased in the frontal cortex and amygdaloid complex. These results led to the conclusion that 5-HT_1A receptors play a significant role in the mechanisms of genetic predisposition to aggressive behavior. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 56, No. 4, pp. 537–542, July–August, 2006.     

Genetic deletion of the adenosine A2A receptor in mice reduces the changes in spinal cord NMDA receptor binding and glucose uptake caused by a nociceptive stimulus

Mice lacking the adenosine A_2A receptor are less sensitive to nociceptive stimuli, and A_2A receptor antagonists have antinociceptive effects. We have previously shown a marked reduction in the behavioural responses to formalin injection in A_2A receptor knockout mice. This may be due to the presence of pronociceptive A_2A receptors on sensory nerves, and if so spinal cords from A_2A receptor knockout mice may have altered neurochemical responses to a nociceptive stimulus. We tested this hypothesis by studying two parameters known to change with spinal cord activity, NMDA glutamate receptor binding and [¹⁴C]-2-deoxyglucose uptake, following intraplantar formalin injection in wild-type and A_2A receptor knockout mice. In naïve untreated A_2A knockout mice [¹⁴C]-2-deoxyglucose uptake in all regions of the spinal cord was significantly lower compared to the wild-type, similar to the reduced NMDA receptor binding that we have previously observed. Following formalin treatment, there was an decrease in [³H]-MK801 binding to NMDA receptors and an increase in [¹⁴C]-2-deoxyglucose uptake in the spinal cords of wild-type mice, and these changes were significantly reduced in the A_2A knockout mice. In addition to altered behavioural responses, there are therefore corresponding reductions in spinal cord neurochemical changes induced by formalin in mice lacking adenosine A_2A receptors. These observations support the hypothesis that activation of A_2A receptors enhances nociceptive input into the spinal cord and suggests a possible role for A_2A antagonists as analgesics.     

Selective adenosine A<Subscript>2A</Subscript>receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects

Background  

Permanent functional deficits following spinal cord injury (SCI) arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A_2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A_2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A_2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites.     

Deletion of the adenosine A(2A) receptor in mice enhances spinal cord neurochemical responses to an inflammatory nociceptive stimulus

Knockout mice lacking the adenosine A_2A receptor are less sensitive to nociceptive stimuli, and this may be due to the presence of pronociceptive A_2A receptors on sensory nerves. In support of this hypothesis, we have recently shown that in A_2A receptor knockout mice there are marked reductions in the changes of two markers of spinal cord neuronal activity, [³H]MK801 binding to NMDA receptors and uptake of [¹⁴C]-2-deoxyglucose, in response to formalin injection. We now report that following a more prolonged inflammatory stimulus, consisting of intraplantar injections of PGE₂ and paw pressure, there was in contrast an increase in [³H]MK801 binding and [¹⁴C]-2-deoxyglucose uptake in the spinal cords of the A_2A receptor knockout mice which was much greater than in the wild-type mice. This increase suggests that when there is a pronounced inflammatory component to the stimulus, loss of inhibitory A_2A receptors on inflammatory cells outweighs the loss of pronociceptive A_2A receptors on peripheral nerves so that overall there is an increase in nociceptive signalling. This implies that although A_2A antagonists have antinociceptive effects they may have only limited use as analgesics in chronic inflammatory pain.     

Caffeine reverses antinociception by oxcarbazepine by inhibition of adenosine A1 receptors: Insights using knockout mice

Oxcarbazepine is an anticonvulsant drug that has been explored as a novel therapeutic agent to treat neuropathic pain in humans. It produces antinociception in several preclinical models of pain, and these actions are blocked by methylxanthine adenosine receptor antagonists which implicates adenosine it its actions. In this study, the antinociceptive effect of oxcarbazepine, and the ability of caffeine to reverse its actions, were examined using the formalin test (2%) in wild-type mice and in mice lacking adenosine A₁ receptors by way of further exploring the involvement of adenosine in its actions. Oxcarbazepine produced dose-related suppression of formalin-evoked flinching responses in wild-type mice following both systemic and intraplantar administration, and this action was reversed by systemic and intraplantar administration of caffeine, respectively. The ability of oxcarbazepine to inhibit flinching after systemic and intraplantar administration was unaltered in homozygous (−/−) and heterozygous (+/−) adenosine A₁ receptor knockout mice. However, caffeine no longer reversed this antinociception. Our results indicate that, while adenosine A₁ receptors are not required for oxcarbazepine to produce antinociception in knockout mice, such receptors are essential in order to see caffeine reversal of this antinociceptive effect.     

In silico study of naphtha [1, 2-d] thiazol-2-amine with adenosine A2A receptor and its role in antagonism of haloperidol-induced motor impairments in mice

Loss of dopaminergic nigrostriatal neurons in the substantia nigra leads to Parkinson's disease (PD). Adenosine A_2A receptors (A_2ARs) have been anticipated as novel therapeutic target for PD. A_2ARs potentiate locomotor behavior and are predominantly expressed in striatum. Naphtha [1, 2-d] thiazol-2-amine (NATA), a tricyclic thiazole have been studied as new anti-Parkinsonian compound. AutoDock analysis and pharmacophore study of NATA with known A_2AR antagonists explicit its efficacy as a possible adenosine receptor antagonist. In vivo pharmacology of NATA showed reduction of haloperidol (HAL)-induced motor impairments in Swiss albino male mice. Relatively elevated levels of dopamine in NATA pre-treated mice are suggestive of its possible role as neuromodulator in PD.     

The GABA<Subscript>A</Subscript> receptor-mediated recurrent inhibition in ventral compared with dorsal CA1 hippocampal region is weaker,decays faster and lasts less

Hippocampal functions appear to be segregated along the dorso-ventral axis of the structure. Differences at the cellular and local neuronal network level may be involved in this functional segregation. In this study the characteristics of CA1 recurrent inhibition (RI) were measured and compared between dorsal (DH, n = 95) and ventral (VH, n = 60) hippocampal slices, using recordings of suprathreshold field potentials. RI strength was estimated as the percentile decrease of the population spike (PS) amplitude evoked with an orthodromic stimulus (at the Schaffer collaterals) when preceded by an antidromic stimulus (at the alveus). Varying the interpulse interval (IPI) between the two stimuli, we estimated RI duration. Alvear stimulation produced significant PS suppression in both VH and DH at every IPI tested, from 10 to 270 ms. Moreover, gradually more oblique DH (but not VH) slices displayed increasing RI, which at IPIs ≤125 ms was reversibly abolished by the GABA_A receptor antagonist picrotoxin (10 μM). The GABA_A-mediated RI, measured under the blockade of GABA_B receptors, was weaker, decayed faster and lasted less in VH compared to DH slices, regardless of the slice orientation. Specifically, in VH compared to DH, the PS suppression at 20 ms was 34.4 ± 4.5% versus 69.9 ± 6.5% (P < 0.001), the time constant of RI decay was 29 ± 2.4 versus 87.5 ± 13.6 ms (P < 0.01) and the duration was 50 versus 125 ms (P < 0.001). Thus, GABA_A-mediated RI may control the CA1 excitatory output less effectively in VH compared to DH. The observed dorso-ventral differences in RI contribute to the longitudinal diversification of the structure and may underlie to some extent the region-specificity of hippocampal functions. Theodoros Petrides and Panagiotis Georgopoulos have equally contributed to the study.     

The role of adenosine A1 receptors in mediating the inhibitory effects of low frequency stimulation of perforant path on kindling acquisition in rats

Low frequency stimulation (LFS) has an inhibitory effect on rapid perforant path kindling acquisition. In the present study the role of adenosine A₁ and A_2A receptors in mediating this inhibitory effect was investigated. Rats were kindled by perforant path stimulation using rapid kindling procedures (12 stimulations per day). LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, and 50–150 μA) was applied to the perforant path immediately after termination of each rapid kindling stimulation. 1,3-Dimethyl-8-cyclopenthylxanthine (CPT; 50 μM), a selective A₁ antagonist and ZM241385 (ZM, 200 μM), a selective A_2A antagonist were daily microinjected into the lateral ventricle 5 min before kindling stimulations. LFS had an inhibitory effect on kindling development. Pretreatment of animals with CPT reduced the inhibitory effect of LFS on kindling rate and suppressed the effects of LFS on potentiation of population EPSP during kindling acquisition. In addition, CPT was able to antagonize the effects of LFS on kindling-induced increase in early (10–50 ms intervals) and late (300–1000 ms intervals) paired pulse depression. ZM pretreatment had no effect on antiepileptogenic effects of LFS in kindling acquisition. In addition, LFS prevented the kindling-induced elevation of cyclic AMP (cAMP) levels in kindled animals. Based on these results, we suggest that the antiepileptogenic effects of LFS on perforant path kindling might be mediated through activation of adenosine A₁, but not A_2A receptors. Moreover, modulation of cAMP levels by LFS may potentially be an important mechanism which explains the anticonvulsant effects of LFS in kindled seizures.     

Caffeine reverses antinociception by amitriptyline in wild type mice but not in those lacking adenosine A1 receptors

Amitriptyline is used to treat neuropathic pain in humans. It produces antinociception in several animal models of pain, and this effect is blocked by methylxanthine adenosine receptor antagonists which implicates adenosine it its actions. Here, the antinociceptive effect of amitriptyline, and the ability of caffeine to reverse it, were examined using the formalin test (a model of persistent pain) in wild type mice and mice lacking the adenosine A₁ receptor (A1R). Amitriptyline produced dose-related suppression of flinching in wild type mice following both systemic and intraplantar drug administration; both of these effects were unaltered in A1R −/− mice. Following systemic administration, caffeine reversed the systemic effect of amitriptyline in wild type, but not A1R −/− mice; −/+ mice exhibited an intermediate effect. Intraplantar administration of caffeine also reversed the effect of intraplantar amitriptyline in A1R +/+, but not in −/− or +/− mice. These results indicate that adenosine A₁ receptors are not required in order for amitriptyline to cause antinociception in mice, but they are required to see caffeine reversal of this antinociceptive effect. When A1Rs are present, actions of amitriptyline may, however, partly depend on A1Rs.     

Functional Characteristics of Serotonin 5-HT<Subscript>2A</Subscript> and 5-HT<Subscript>2C</Subscript> Receptors in the Brain and the Expression of the 5-HT<Subscript>2A</Subscript> and 5-HT<Subscript>2C</Subscript> Receptor Genes in Aggressive and Non-Aggressive Rats

The functional activity of serotonin 5-HT_2A and 5-HT_2C receptors and the expression of the genes encoding them were studied in Norway rats bred for 60 generations for the presence and absence of high levels of stress-evoked aggression to humans. There were no significant differences in the levels of 5-HT_2A receptor mRNA in the midbrain, frontal cortex, and hippocampus and the extents of head twitching evoked by the 5-HT_2A agonist DOI in rats with and without genetically determined high levels of aggression. Administration of the selective 5-HT_2C agonist MK-212 weakened reflex startle in response to an acoustic signal (the acoustic startle response) in non-aggressive animals but had no significant effects on the response in aggressive animals. Increases in the level of 5-HT_2C receptor mRNA were seen in the frontal cortex and hippocampus in non-aggressive rats as compared with aggressive animals. Increases in the expression of the 5-HT_2C receptor gene and the functional state of 5-HT_2C receptors were seen in the brains of non-aggressive rats, without any changes in the 5-HT_2A receptor mRNA level or receptor sensitivity; this is evidence for the involvement of 5-HT_2C receptors in the mechanisms inhibiting fear-evoked aggressive behavior.     

Involvement of Presynaptic 5-HT<Subscript>1A</Subscript> Receptors in Immunomodulation in Conditions of Psychoemotional Tension

The development of an immune reaction in CBA mice during activation and blockade of serotonin 1A (5-HT_1A) autoreceptors with highly selective agents has characteristic features depending on the behavioral stereotype formed. The 5-HT_1A receptor agonist 8-OH-DPAT (0.1 mg/kg 15 min before immunization) did not alter the number of IgM antibody-forming cells in the spleen at the peak of the immune reaction (day 4) in aggressive mice, but increased the number in submissive mice, in which the immune response without treatment was lower than that in aggressive animals. Blockade of the same receptor type with WAY-100635 (0.1 mg/kg 30 min before immunization) led to a decrease in the immune response in animals with aggressive behavior and an increase in submissive animals. The question of the influences of agents acting on presynaptic 5-HT_1A somatodendritic autoreceptors on the immune response, depending on the functional state of 5-HT_1A receptors and the balance of activities in the serotoninergic and dopaminergic systems as a whole, is discussed.     

Effect of Selective Agonist of Serotonin 5-HT<Subscript>1A</Subscript> Receptors on Defensive Behavior in Mice with Different Predisposition to Catalepsy

We studied the effect of activation of serotonin 5-HT_1A receptors with selective agonist 8-OHDPAT (0.1, 0.5, and 1.0 mg/kg) on intraspecies aggression and freezing reaction (catalepsy) in male mice of catalepsy-resistant AKR/J and two catalepsy-prone strains CBA/Lac and congenic AKR.CBA-D13Mit76. The latter strain differs from AKR strain only by terminal chromosome 13 fragment transferred from CBA strain and containing a locus determining predisposition to catalepsy and a gene encoding 5-HT_1A receptor. 8-OH-DPAT in a low dose (0.1 mg/kg) affecting primarily presynaptic receptors suppressed aggressive behavior in CBA mice, but had no effect on the time of cataleptic freezing. At the same time, this dose of the drug produced no significant effect on aggression in AKR and AKR.CBA-D13Mit76 mice, but significantly attenuated freezing in AKR.CBA-D13Mit76 mice. High doses of 8-OHDPAT (0.5 and 1 mg/kg) which affected mainly postsynaptic receptors inhibited catalepsy in CBA and AKR.CBA-D13Mit76 mice and in a dose of 1 mg/kg it suppressed aggression in all tested mouse strains. We concluded that the genome of the recipient strain (AKR) modulated the involvement of 5-HT_1A receptors into the regulation of aggression and catalepsy in mice.     

Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease

The aim of this review is to summarize and critically discuss the complex role played by adenosine A_2A receptors (A_2ARs) in Huntington's disease (HD). Since A_2ARs are mainly localized on the neurons, which degenerate early in HD, and given their ability to stimulate glutamate outflow and inflammatory gliosis, it was hypothesized that they could be involved in the pathogenesis of HD, and that A_2AR antagonists could be neuroprotective. This was further sustained by the demonstration that A_2ARs and underlying signaling systems undergo profound changes in cellular and animal models of HD. More recently, however, the equation A_2A receptor blockade = neuroprotection has appeared too simplistic. First, it is now definitely clear that, besides mediating ‘bad’ responses (for example, stimulation of glutamate outflow and excessive glial activation), A_2ARs also promote ‘good’ responses (such as trophic and antinflammatory effects). This implies that A_2AR blockade results either in pro-toxic or neuroprotective effects according to the mechanisms involved in a given experimental model. Second, since HD is a chronically progressive disease, the multiple mechanisms involving A_2ARs may play different relative roles along the degenerative process. Such different mechanisms can be influenced by A_2AR activation or blockade in different ways, even leading to opposite outcomes depending on the time of agonist/antagonist administration. The number, and the complexity, of the possible scenarios is further increased by the influence of mutant Huntingtin on both the expression and functions of A_2ARs, and by the strikingly different effects mediated by A_2ARs expressed by different cell populations within the brain.     

The adenosine A<Subscript>2A</Subscript> receptor agonist CGS 21680 fails to ameliorate the course of dextran sulphate-induced colitis in mice

OBJECTIVE: In this study we investigated the effect of CGS 21680 (2-p-(2-Carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosine hydrochloride), an adenosine A2A receptor agonist, in a model of dextran sulphate sodium (DSS)-induced colitis. METHODS: NMRI mice were fed 5 % (w/v) DSS, and were treated intraperitoneally with 0.5 mg/kg CGS 21680 or vehicle for 10 days. Changes of bodyweight, colon length, the incidence of rectal bleeding, levels of macrophage inflammatory protein (MIP)-1alpha, MIP-2, interferon gamma, interleukin (IL)-1beta, IL-12 and tumour necrosis factor-alpha from homogenates of colon biopsies, and the release of [3H]acetylcholine (ACh) from longitudinal muscle strip were determined. RESULTS: DSS significantly decreased bodyweight, colon length, and it increased the incidence of rectal bleeding and levels of MIP-1alpha, MIP-2 and IL-1beta compared to DSS-untreated animals. CGS 21680 had no effect on these changes. No change could be observed in release of ACh in DSS-induced colitis with or without CGS 21680. CONCLUSION: In summary, CGS 21680 is ineffective in ameliorating DSS-induced colitis in mice.