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1.
In Parkinson’s disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A 2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist. The drugs were given alone or in combination and rats were placed in an open-field for behavioural monitoring. Video recordings were automatically analysed. Five different behaviours were scored: distance traveled, ipsi- and contraversive turns, body position, and space occupancy. The results show that A 2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide. Instead the treated rats maintained a straight body position, were able to shift from one direction to the other and occupied a significantly larger space in the arena. The highest “Tozadenant/Radiprodil” dose combination significantly increased all five behavioural parameters recorded compared to rats treated with vehicle or the same doses of the drugs alone. Our data suggest that the A 2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation. If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD. 相似文献
3.
SCH 58261 is a reported adenosine A 2A receptor antagonist, which is active in rat in vivo models of Parkinson’s Disease upon ip administration. However, it has poor selectivity versus the A 1 receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A 2A receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A 2A receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay. 相似文献
4.
Cellular elements of maturing brain are vulnerable to insults, which lead to neurodevelopmental defects. There are no established treatments at present. Here we examined the efficacy of selective adenosine A 2A receptor inhibitor SCH58261 to combat brain injury, particularly oligodendrocyte (OL) lineage cells, in young rats. Wistar rats (n = 24, 6.5 days old) were randomly divided into equal groups of four. The sham (SHAM) group received no treatment, the vehicle (VEHICLE) group received 0.1% dimethylsufoxide, the injury (INJ) group was exposed to oxygen-glucose deprivation insult, and the injury+SCH58261 (INJ+SCH58261) group was exposed to the insult and received 1 μM SCH58261. Immunocytochemical experiments revealed that there was a significant reduction in the populations of mature OL (MBP + OLs) and immature OL precursors (NG2 + OPCs) in the INJ group compared to SHAM group. Furthermore, there was also a significant increase in the percent of apoptotic MBP + OL and NG2 + OPC populations as evidenced by TUNEL assay. In addition, there was a significant reduction in the proliferation rate among NG2 + OPCs, which was confirmed by BrdU immunostaining. On the other hand, treatment with SCH58261 significantly enhanced survival, evidenced by the reduction in apoptotic indices for both cell types, and it is preserved the NG2 + OPC proliferation. Activation of adenosine A 2A receptors may contribute to OL lineage cell loss in association with decreased mitotic behavior of OPCs in neonatal brains upon injury. Future investigations assessing ability of SCH58261 to regenerate myelin will provide insights into its wider clinical relevance. 相似文献
5.
Background Caffeine, a nonselective adenosine A 1 and A 2A receptor antagonist, is the most widely used psychoactive substance in the world. Evidence demonstrates that caffeine and
selective adenosine A 2A antagonists interact with the neuronal systems involved in drug reinforcement, locomotor sensitization, and therapeutic effect
in Parkinson's disease (PD). Evidence also indicates that low doses of caffeine and a selective adenosine A 2A antagonist SCH58261 elicit locomotor stimulation whereas high doses of these drugs exert locomotor inhibition. Since these
behavioral and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic pathways which project to
the striatum, we hypothesize that low doses of caffeine and SCH58261 may modulate the functions of dopaminergic neurons in
the striatum. 相似文献
6.
SCH 58261 is a reported adenosine A 2A receptor antagonist which is active in rat in vivo models of Parkinson’s Disease upon ip administration. However, it has poor selectivity versus the A 1 receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A 2A receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A 2A receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson’s Disease, and has aqueous solubility of 100 μM at physiological pH. 相似文献
7.
6-Hydroxydopamine (6-OHDA) is the most used toxin in experimental Parkinson’s disease (PD) models. 6-OHDA shows high affinity for the dopamine transporter and once inside the neuron, it accumulates and undergoes non-enzymatic auto-oxidation, promoting reactive oxygen species (ROS) formation and selective damage of catecholaminergic neurons. In this way, our group has established a 6-OHDA in vitro protocol with rat striatal slices as a rapid and effective model for screening of new drugs with protective effects against PD. We have shown that co-incubation with guanosine (GUO, 100 μM) prevented the 6-OHDA-induced damage in striatal slices. As the exact GUO mechanism of action remains unknown, the aim of this study was to investigate if adenosine A1 (A1R) and/or A2A receptors (A2AR) are involved on GUO protective effects on striatal slices. Pre-incubation with DPCPX, an A1R antagonist prevented guanosine effects on 6-OHDA-induced ROS formation and mitochondrial membrane potential depolarization, while CCPA, an A1R agonist, did not alter GUO effects. Regarding A2AR, the antagonist SCH58261 had similar protective effect as GUO in ROS formation and mitochondrial membrane potential. Additionally, SCH58261 did not affect GUO protective effects. The A2AR agonist CGS21680, although, completely blocked GUO effects. Finally, the A1R antagonist DPCPX, and the A2AR agonist CGS21680 also abolished the preventive guanosine effect on 6-OHDA-induced ATP levels decrease. These results reinforce previous evidence for a putative interaction of GUO with A1R-A2AR heteromer as its molecular target and clearly indicate a dependence on adenosine receptors modulation to GUO protective effect. 相似文献
8.
Adenosine A 2A receptors antagonists produce neuroprotective effects in animal models of Parkinson’s disease (PD). As neuroinflammation is involved in PD pathogenesis, both neuronal and glial A 2A receptors might participate to neuroprotection. We employed complementary pharmacologic and genetic approaches to A 2A receptor inactivation, in a multiple MPTP mouse model of PD, to investigate the cellular basis of neuroprotection by A 2A antagonism. MPTP·HCl (20 mg/kg daily for 4 days) was administered in mice treated with the A 2A antagonist SCH58261, or in conditional knockout mice lacking A 2A receptors on forebrain neurons (fbnA 2AKO mice). MPTP‐induced partial loss of dopamine neurons in substantia nigra pars compacta (SNc) and striatum (Str), associated with increased astroglial and microglial immunoreactivity in these areas. Astroglia was similarly activated 1, 3, and 7 days after MPTP administration, whereas maximal microglial reactivity was detected on day 1, returning to baseline 7 days after MPTP administration. SCH58261 attenuated dopamine cell loss and gliosis in SNc and Str. Selective depletion of A 2A receptors in fbnA 2AKO mice completely prevented MPTP‐induced dopamine neuron degeneration and gliosis in SNc, and partially counteracted gliosis in Str. Results provide evidence of a primary role played by neuronal A 2A receptors in neuroprotective effects of A 2A antagonists in a multiple MPTP injections model of PD. With the symptomatic antiparkinsonian potential of several A 2A receptor antagonists being pursued in clinical trials, this study adds to the rationale for broader clinical benefit and use of these drugs early in the treatment of PD. 相似文献
9.
Novel thiazolotriazolopyrimidine derivatives ( 23–33) designed as potential adenosine A 2A receptor (A 2AR) antagonists were synthesized. Molecular docking studies revealed that all compounds ( 23–33) exhibited strong interaction with A 2AR. The strong interaction of the compounds ( 23–33) with A 2AR in silico was confirmed by their high binding affinity with human A 2AR stably expressed in HEK293 cells using radioligand-binding assay. The compounds 24–26 demonstrated substantial binding affinity and selectivity for A 2AR as compared to SCH58261, a standard A 2AR antagonist. Decrease in A 2AR-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A 2AR antagonist potential of the compounds 24–26. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 24–26 further supports their role in the alleviation of PD symptoms. 相似文献
10.
In a previous work we have shown that exposure to aluminum (Al) chloride (AlCl 3) enhanced the neurotoxicity of the amyloid beta 25-35 fragment (Abeta 25-35) in neuroblastoma cells and affected the expression of Alzheimer's disease (AD)-related genes. Caffein, a compound endowed with beneficial effects against AD, exerts neuroprotection primarily through its antagonist activity on A 2A adenosine receptors (A 2AR), although it also inhibits A 1Rs with similar potency. Still, studies on the specific involvement of these receptors in neuroprotection in a model of combined neurotoxicity (Abeta 25-35 + AlCl 3) are missing. To address this issue, cultured SH-SY5Y cells exposed to Abeta 25-35 + AlCl 3 were assessed for cell viability, morphology, intracellular ROS activity and expression of apoptosis-, stress- and AD-related proteins. To define the role of A 1R and A 2ARs, pretreatment with caffein, specific receptor antagonists (DPCPX or SCH58261) or siRNA-mediated gene knockdown were delivered. Results indicate that AlCl 3 treatment exacerbated Abeta 25-35 toxicity, increased ROS production, lipid peroxidation, β-secretase-1 (BACE1) and amyloid precursor protein (APP). Interestingly, SCH58261 successfully prevented toxicity associated to Abeta 25-35 only, whereas pretreatment with both DPCPX and SCH58261 was required to fully avert Abeta 25-35 + AlCl 3-induced damage, suggesting that A 1Rs might also be critically involved in protection during combined toxicity. The effects of caffein were mimicked by both N-acetyl cysteine, an antioxidant, and desferrioxamine, likely acting through distinct mechanisms. Altogether, our data establish a novel protective function associated with A 1R inhibition in the setting of combined Abeta 25-35 + AlCl 3 neurotoxicity, and expand our current knowledge on the potential beneficial role of caffein to prevent AD progression in subjects environmentally exposed to aluminum. 相似文献
11.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed. N
6-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is a N 6-substitued adenosine analog. Here we describe an investigation of the effects and mechanisms of B2 on chemical convulsant-induced seizures. Seizures were induced in mice by administration of 4-aminopyridine (4-AP), pentylenetetrazol (PTZ), picrotoxin, kainite acid (KA), or strychnine. B2 has a dose-related anticonvulsant effect in these chemical-induced seizure models. The protective effects of B2 include increased latency of seizure onset, decreased seizure occurrence, shorter seizure duration and reduced mortality rate. Radioligand binding and cAMP accumulation assays indicated that B2 might be a functional ligand for both adenosine A 1 and A 2A receptors. Furthermore, DPCPX, a selective A 1 receptor antagonist, but not {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304"}}SCH58261, a selective A 2A receptor antagonist, blocked the anticonvulsant effect of B2 on PTZ-induced seizure. c-Fos is a cellular marker for neuronal activity. Immunohistochemical and western blot analyses indicated that B2 significantly reversed PTZ-induced c-Fos expression in the hippocampus. Together, these results indicate that B2 has significant anticonvulsant effects. The anticonvulsant effects of B2 may be attributed to adenosine A 1 receptor activation and reduced neuronal excitability in the hippocampus. These observations also support that the use of adenosine receptor agonist may be a promising approach for the treatment of epilepsy. 相似文献
12.
Latest results on the action of adenosine A 2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia
possess high levels of adenosine A 2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus,
and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A 2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A 2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The
experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with
simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A 2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A 2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility
during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A 2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects.
In combination therapy, the adenosine A 2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration
of adenosine A 2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It
was demonstrated in various animal models that inhibition of adenosine A 2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or
stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor
of adenosine A 2A receptors, as an anti-Parkinson drug. 相似文献
13.
We have investigated the role of N-methyl- d-aspartate receptors (NMDARs) and γ-aminobutyric acid receptors type A (GABA ARs) at an early stage of P19 neuronal differentiation. The subunit expression was profiled in 24-hour intervals with RT-PCR and functionality of the receptors was verified via fluo-3 imaging of Ca 2+ dynamics in the immature P19 neurons showing that both NMDA and GABA excite neuronal bodies, but only polyamine-site sensitive NMDAR stimulation leads to enhanced Ca 2+ signaling in the growth cones. Inhibition of NR1/NR2B NMDARs by 1 μM ifenprodil severely impaired P19 neurite extension and fasciculation, and this negative effect was fully reversible by polyamine addition. In contrast, GABA AR antagonism by a high dose of 200 μM bicuculline had no observable effect on P19 neuronal differentiation and fasciculation. Except for the differential NMDAR and GABA AR profiles of Ca 2+ signaling within the immature P19 neurons, we have also shown that inhibition of NR1/NR2B NMDARs strongly decreased mRNA level of NCAM-180, which has been previously implicated as a regulator of neuronal growth cone protrusion and neurite extension. Our data thus suggest a critical role of NR1/NR2B NMDARs during the process of neuritogenesis and fasciculation of P19 neurons via differential control of local growth cone Ca 2+ surges and NCAM-180 signaling. 相似文献
14.
Glucose-sensitive neurons in the lateral hypothalamic area produce orexin-A (OxA) as well as orexin-B (OxB) and send their axons to the spinal dorsal horn, which predominantly expresses orexin receptor-1 (OX-1), showing a higher sensitivity to OxA. The purpose of the present study was to assess the effects of OxA on the induction of a novel form of activity-dependent reflex potentiation, spinal reflex potentiation (SRP), in the pelvic-urethral reflex activity. External urethra sphincter electromyogram in response to pelvic afferent nerve test stimulation (TS; 1/30 Hz) or repetitive stimulation (RS; 1 Hz) was recorded in anesthetized rats. TS evoked a baseline reflex activity, whereas RS produced SRP, which was abolished by intrathecal OxA (30 nM, 10 mul). Intrathecal SB-408124 (10 muM, 10 mul), an OX-1 antagonist, reversed the abolition on SRP caused by OxA. Although there is, so far, no NR2A- and NR2B-specific agonist available, N-methyl-d-aspartate (NMDA) reversed the abolition on the RS-induced SRP caused by the co-administration of OxA and Co-101244 (30 nM, 10 mul; an NMDA NR2B subunit antagonist), but it did not reverse the abolition by the co-administration of OxA and PPPA (300 nM, 10 mul; an NMDA NR2A subunit antagonist). In conclusion, the activation of descending orexinergic fibers may inhibit the repetitive afferent input-induced central sensitization of pelvic-urethral reflex activity and urethra hyperactivity, indicating that spinal orexinergic neural transmission may be a novel target for the treatment of patients with neuropathetic or postinflammatory pain of pelvic origin. 相似文献
15.
We found that prostaglandin (PG) D 2, the most abundant PG produced in the central nervous system (CNS), exhibited anxiolytic-like activity at a dose of 10–100 pmol/mouse after intracerebroventricular (i.c.v.) administration in the elevated plus-maze test in mice. A DP 1 receptor-selective agonist, BW245C, mimicked the anxiolytic-like activity of PGD 2, while a DP 2 receptor agonist 13,14-dihydro-15-keto-PGD 2 was inactive. The anxiolytic-like activity of PGD 2 was blocked by a DP 1 antagonist, BWA868C, suggesting that PGD 2-induced anxiolytic-like activity was mediated by the DP 1 receptor. Adenosine A 2A or GABA A receptor antagonists, SCH58261 or bicuculline, respectively, also blocked its anxiolytic-like activity. Taken together, centrally administered PGD 2 may induce anxiolytic-like activity via the A 2A and GABA A receptors, downstream of the DP 1 receptor. 相似文献
16.
Stimulation of A 2A receptors (A 2A R) coupled to G s/olf protein activates Adenylyl cyclase (AC) leading to the release of cAMP which activates the cAMP-dependent PKA phosphorylation. The possible role of A 2A R in the modulation of free cytosolic Ca 2+ concentration ([Ca 2+] i) involving IP 3, cAMP and PKA was investigated in HEK 293-A 2A R. The levels of IP 3 and cAMP were observed by enzyme immunoassay detection method and [Ca 2+] i using Fluo-4 AM. Moreover, cAMP-dependent PKA was determined using the PKA Colorimetric Activity Kit. We observed that the cells pre-treated with A 2A R agonist NECA showed increased levels of cAMP, PKA, IP 3 and [Ca 2+] i levels. However, the reverse effect was observed with A 2A R antagonists (ZM241385 and caffeine). Blocking the G αq/PLC/DAG/IP 3 pathway with neomycin, a PLC inhibitor did not affect the modulation of IP 3 and [Ca 2+] i levels in HEK 293-A 2A R cells. To investigate the G αi/AC/cAMP/PKA, HEK 293-A 2A R cells pre-treated with pertussis toxin followed by forskolin in the presence of A 2A R agonist (NECA) showed no effect on cAMP levels. Further, G αs/AC/cAMP/PKA pathway was investigated to elucidate the role of cAMP-dependent PKA in IP 3 mediated [Ca 2+] i modulation. In the HEK 293-A 2A R cells pre-treated with PKA inhibitor KT5720 and treated with NECA led to inhibit the IP 3 and [Ca 2+] i levels. The study distinctly demonstrated that A 2A R modulates IP 3 levels to release the [Ca 2+] i via cAMP-dependent PKA. The role of A 2A R mediated G αs pathway inducing IP 3 mediated [Ca 2+] i release may open new avenues in the therapy of neurodegenerative disorder. 相似文献
17.
Herein we describe the discovery of a series of novel adenosine A 2A receptor antagonists. A successful hit-to-lead optimization of an HTS hit led to replacement of a metabolically labile ester moiety with a heteroaromatic group. A compound from the series, (cyclopropanecarboxylic acid [5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-amide, compound 13), was shown to be effective in reversing haloperidol-induced hypolocomotion, a model of motor dysfunction in Parkinson’s Disease. 相似文献
18.
A rapid and sensitive spectrophotometric assay for venom phospholipase A 2 based on the hemolysis of guinea pig erythrocytes in the presence of decomplemented serum and cardiotoxin (direct lytic factor) is described. This assay is particularly useful for rapid multisample analyses, such as those used in monitoring chromatography fractions, and is specific for phospholipase A 2 in she presence of other potentially hemolytic venom components. The hemolytic mechanism is shown to be a combination of the action of lysophospholipids liberated from lipoproteins in the serum and the synergistic action of phospholipase A 2 and cardiotoxin on the erythrocyte membrane. 相似文献
19.
Novel 2-thioxothiazole derivatives ( 6– 19) as potential adenosine A 2A receptor (A 2AR) antagonists were synthesized. The strong interaction of the compounds ( 6– 19) with A 2AR in docking study was confirmed by high binding affinity with human A 2AR expressed in HEK293T cells using radioligand-binding assay. The compound 19 demonstrated very high selectivity for A 2AR as compared to standard A 2AR antagonist SCH58261. Decrease in A 2AR-coupled release of endogenous cAMP in treated HEK293T cells demonstrated in vitro A 2AR antagonist potential of the compound 19. Attenuation in haloperidol-induced impairment (catalepsy) in Swiss albino male mice pre-treated with compound 19 is evocative to explore its prospective in therapy of PD. 相似文献
20.
N-Methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission is thought to play a central role in the development of alcohol dependence and this alteration is supposed to be due to a differential up-regulation of the NR2B type of subunits. In this work, we examined the effect of some known (CP-101,606; CI-1041 and Co-101,244) and novel indole-2-carboxamide derivative NR2B subunit selective NMDA receptor antagonists (SSNAs) (RG-13579 and RG-1103) on the neurotoxic effect of withdrawal in ethanol pre-treated cultures of rat cortical neurones. The extent of neurotoxicity was estimated by measuring the activity of lactate dehydrogenase (LDH) that was released into the culture medium during the 24h withdrawal period. Here, we demonstrate that NR2B SSNAs given in the course of the withdrawal potently reduced the LDH release in ethanol pre-treated cultures. One of our novel compound, RG-1103, proved to be more potent than the reference NR2B SSNAs tested in this work having similar potency as the most potent but non-subunit selective NMDA receptor antagonist dizocilpine (MK-801). Acamprosate, a currently used therapeutic drug for the treatment of alcoholism was also effective although only in high micromolar concentrations. According to these observations, NR2B SSNAs are potent inhibitors of ethanol-withdrawal-induced neurotoxicity and considering that these agents have acceptable side effect profiles, they could be promising therapeutic candidates in the pharmacotherapy for physical signs of acute alcohol-withdrawal and associated neuronal damage. 相似文献
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