The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform
Jana Sawynok - One of the best experts on this subject based on the ideXlab platform.
-
potentiation of formalin evoked Adenosine release by an Adenosine kinase Inhibitor and an Adenosine Deaminase Inhibitor in the rat hind paw a microdialysis study
European Journal of Pharmacology, 2000Co-Authors: Xue Jun Liu, Thomas D. White, Jana SawynokAbstract:The present study examined the effects of local subcutaneous administration of formalin on Adenosine release from the rat hind paw, and the effects of Inhibitors of Adenosine metabolism on such release. Microdialysis probes were inserted into the subcutaneous tissue of the plantar surface of rat hind paws. Samples were collected every 10 min at a perfusion rate of 2 microl/min and high performance liquid chromatography was used to measure Adenosine levels. At lower concentrations of formalin (0.5-2.5%), a significant increase in Adenosine levels was observed in the first 10 min after formalin injection, while at the highest concentration of formalin (5%), the increase in Adenosine release was observed over 60 min. Co-administration of the Adenosine kinase Inhibitor 5'-amino-5'-deoxyAdenosine (100 nmol) with formalin, significantly increased Adenosine release evoked by 0.5-1.5% formalin, but did not produce a further enhancement of release evoked by 5% formalin. The Adenosine Deaminase Inhibitor 2'-deoxycoformycin (100 nmol) significantly increased Adenosine levels at 5% formalin but had no effect at lower concentrations of formalin. In confirmation of previous studies, subcutaneous injection of formalin (0.5-5%) produced a characteristic biphasic concentration-related expression of nociceptive behaviours and an increase in paw volume. This study directly demonstrates that formalin can evoke a concentration-dependent local release of Adenosine from the rat hind paw. The ability of an Adenosine kinase Inhibitor and an Adenosine Deaminase Inhibitor to modulate this release is dependent on substrate Adenosine concentrations.
-
antinociceptive and anti inflammatory properties of an Adenosine kinase Inhibitor and an Adenosine Deaminase Inhibitor
European Journal of Pharmacology, 1999Co-Authors: Anthony Poon, Jana SawynokAbstract:Spinal administration of an Adenosine kinase Inhibitor, alone or in combination with an Adenosine Deaminase Inhibitor, produces antinociception in inflammatory pain tests. In the present study, we examined the antinociceptive and anti-inflammatory effects produced by the peripheral (intraplantar) administration of 5'-amino-5'-deoxyAdenosine (an Adenosine kinase Inhibitor), 2'-deoxycoformycin (an Adenosine Deaminase Inhibitor), and combinations of both agents in the carrageenan-induced thermal hyperalgesia and paw oedema model in the rat. When injected in the ipsilateral paw immediately prior to carrageenan injection, both agents produced antinociception only at the highest dose (1 micromol), whereas a reduction in paw swelling was evident at a lower dose (300 nmol). Significant augmentation in both the antinociceptive and anti-inflammatory effects was seen when 5'-amino-5'-deoxyAdenosine and 2'-deoxycoformycin were co-administered in equimolar doses at all dose levels. Both effects were mediated via activation of Adenosine receptors, as indicated by blockade by an Adenosine receptor antagonist. When administered into the contralateral paw, 1 micromol 5'-amino-5'-deoxyAdenosine+1 micromol 2'-deoxycoformycin produced prominent antinociception, indicating a systemic drug activity. There was only a modest reduction in paw oedema in the carrageenan-injected (ipsilateral) paw, suggesting that much of this activity was locally mediated. Reversal of systemic effects on thermal thresholds by an intrathecal Adenosine receptor antagonist implicates a spinal site of action in this instance. An ipsilateral administration of 1 micromol 5'-amino-5'-deoxyAdenosine, but not 1 micromol 2'-deoxycoformycin, reduced carrageenan-induced c-Fos expression in the spinal dorsal horn, and this was further reduced by the peripheral co-injection of the two agents. These results provide evidence for a predominantly spinal antinociceptive effect and a predominantly peripheral anti-inflammatory effect produced by Inhibitors of Adenosine kinase and Adenosine Deaminase.
-
peripheral antinociceptive effect of an Adenosine kinase Inhibitor with augmentation by an Adenosine Deaminase Inhibitor in the rat formalin test
Pain, 1998Co-Authors: Jana Sawynok, Allison Reid, Anthony PoonAbstract:Abstract This study examined the ability of an Adenosine kinase Inhibitor (5′-amino-5′-deoxyAdenosine; NH2dAD), an Adenosine Deaminase Inhibitor (2′-deoxycoformycin), and combinations of these agents to produce a peripheral modulation of the pain signal in the low concentration formalin model. Drugs were administered in combination with 0.5% formalin, or into the contralateral hindpaw to test for systemic effects, and episodes of flinching behaviors determined. Coadministration of NH2dAD 0.1–100 nmol with formalin produced antinociception as revealed by an inhibition of flinching behaviors. This action was peripherally mediated as it was not seen following contralateral administration of the NH2dAD, and was due to accumulation of Adenosine and activation of cell surface Adenosine receptors as it was blocked by the Adenosine receptor antagonist caffeine. Antinociception was intensity-dependent, as it was not seen when higher concentrations of formalin (0.75%, 1.5%) were used. The coadministration of the selective Adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine revealed the presence of an Inhibitory tone of Adenosine when the intrinsic antinociceptive effect of NH2dAD was obscured by the solvent or the stimulus intensity. 2′-Deoxycoformycin 0.1–100 nmol did not produce any intrinsic effect, but 100 nmol coadministered with low concentrations of NH2dAD, which lacked an intrinsic effect, augmented antinociception by NH2dAD. Again, this was a peripheral rather than a systemic response. The combined action of the Adenosine kinase and Deaminase Inhibitors was completely reversed by coadministration of caffeine. Antinociception with NH2dAD is observed at higher concentrations of formalin in second trial experiments. This study demonstrates a peripheral antinociceptive action mediated by endogenous Adenosine which accumulates following the peripheral inhibition of Adenosine kinase; this action is due to activation of an Adenosine A1 receptor.
-
antinociception by Adenosine analogs and Inhibitors of Adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat
Pain, 1998Co-Authors: Anthony Poon, Jana SawynokAbstract:Abstract The present study examined the spinal antinociceptive effects of Adenosine analogs and Inhibitors of Adenosine kinase and Adenosine Deaminase in the carrageenan-induced thermal hyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of Adenosine kinase Inhibitors by an Adenosine Deaminase Inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2 mg/100 μ l), which consistently produced significant paw swelling and thermal hyperalgesia. Drugs were administered intrathecally, either by acute percutaneous lumbar puncture (individual agents and combinations) or via an intrathecal catheter surgically implanted 7–10 days prior to drug testing (antagonist experiments). N 6 -cyclohexylAdenosine (CHA; Adenosine A 1 receptor agonist; 0.01–1 nmol), 2-[ p -(2-carboxyethyl)phenylethylamino]-5′- N -ethylcarboxamidoAdenosine (CGS21680; Adenosine A 2A receptor agonist; 0.1–10 nmol), 5′-amino-5′-deoxyAdenosine (NH 2 dAdo; Adenosine kinase Inhibitor; 10–300 nmol), and 5-iodotubercidin (ITU; Adenosine kinase Inhibitor; 0.1–100 nmol) produced, to varying extents, dose-dependent antinociception. No analgesia was seen following injection of 2′-deoxycoformycin (dCF; an Adenosine Deaminase Inhibitor; 100–300 nmol). Reversal of drug effects by caffeine (non-selective Adenosine A 1 /A 2 receptor antagonist; 515 nmol) confirmed the involvement of the Adenosine receptor, while antagonism by 8-cyclopentyl-1,3-dimethylxanthine (CPT; Adenosine A 1 receptor antagonist; 242 nmol), but not 3,7-dimethyl-1-propargylxanthine (DMPX; Adenosine A 2A receptor antagonist; 242 nmol), evidenced an Adenosine A 1 receptor mediated spinal antinociception by NH 2 dAdo. dCF (100 nmol), which was inactive by itself, enhanced the effects of 10 nmol and 30 nmol NH 2 dAdo. Enhancement of the antinociceptive effect of ITU by dCF was less pronounced. None of the antinociceptive drug regimens had any effect on paw swelling. These results demonstrate that both directly and indirectly acting Adenosine agents, when administered spinally, produce antinociception through activation of spinal Adenosine A 1 receptors in an inflammatory model of thermal hyperalgesia. The spinal antinociceptive effects of selected Adenosine kinase Inhibitors can be significantly augmented when administered simultaneously with an Adenosine Deaminase Inhibitor.
-
Modulation of Adenosine release from rat spinal cord by Adenosine Deaminase and Adenosine kinase Inhibitors.
Brain Research, 1995Co-Authors: Krystyna Golembiowska, Thomas D. White, Jana SawynokAbstract:Adenosine, a modulator of pain processing in the spinal cord, is metabolized by Adenosine kinase and Adenosine Deaminase. In this study we determined which of these mechanisms is more important for the regulation of endogenous Adenosine levels in the rat spinal cord. The effects of the Adenosine kinase Inhibitors, 5′-deoxyAdenosine (NH2dAD) and iodotubercidin (IOT), and the Adenosine Deaminase Inhibitor, 2′-deoxycoformycin (DCF), on Adenosine release in a spinal cord superfusion model were studied. DCF markedly increased basal Adenosine levels detected in perfusates and was more potent than NH2dAD and IOT in this regard. Coadministration of DCF with NH2dAD produced an enhanced effect compared to the Inhibitors alone. NH2dAD, but not DCF, potentiated morphine-evoked Adenosine release. These results suggest that Adenosine Deaminase may be the predominant pathway for Adenosine metabolism in this experimental model.
Isao Nakanishi - One of the best experts on this subject based on the ideXlab platform.
-
Binding free energy calculations of Adenosine Deaminase Inhibitor and the effect of methyl substitution in Inhibitors.
Journal of chemical information and modeling, 2009Co-Authors: Takahiro Kosugi, Isao Nakanishi, Kazuo KitauraAbstract:The binding affinity of an Inhibitor is often improved ten times or more by introducing a simple substituent, such as a methyl group or a chlorine atom. We have investigated this phenomenon in the case of Adenosine Deaminase (ADA) Inhibitors using molecular dynamics (MD) simulations and binding free energy calculations, by the linear interaction energy (LIE) method. For MD simulations, the coordination bond parameters and partial charges of atoms around the zinc ion in ADA have been determined by referring to ab initio MO calculations. The calculated binding free energies for seven Inhibitors agreed well with the experimental ones, with a maximum error of 1.2 kcal/mol. The effect of methyl substitution in Inhibitor molecules was examined on the basis of MD trajectories. It is suggested that the increase in binding affinity is caused by both van der Waals stabilizations by amino acid residues in contact with the introduced methyl group and through favored overall interactions with surrounding residues in t...
-
Anti-inflammatory activity of non-nucleoside Adenosine Deaminase Inhibitor FR234938.
European journal of pharmacology, 2006Co-Authors: Masako Kuno, Nobuo Seki, Susumu Tsujimoto, Isao Nakanishi, Takayoshi Kinoshita, Katsuya Nakamura, Tadashi Terasaka, Nobuya Nishio, Akihiro Sato, Takashi FujiiAbstract:Adenosine has anti-inflammatory activity. Adenosine Deaminase (EC 3.5.4.4) metabolizes extracellular Adenosine, resulting in an exacerbation of inflammation. Consequently, it was hypothesized that Adenosine Deaminase Inhibitors produce anti-inflammatory activity by increasing extracellular Adenosine concentration. This group recently developed a non-nucleoside Adenosine Deaminase Inhibitor, FR234938, by using rational structure-based drug design. FR234938 inhibits recombinant human Adenosine Deaminase enzyme competitively. FR234938 inhibits interleukin (IL)-6-dependent immunoglobulin (Ig) M production by SKW6.4 cells, in the presence of Adenosine. Inhibitory effect of FR234938/Adenosine combination is blocked by an A2a Adenosine receptor antagonist. FR234938 also inhibits anti-type II collagen delayed type hypersensitivity (DTH) in a dose-dependent manner, both in the presence and absence of recombinant human Adenosine Deaminase. Moreover, FR234938 inhibits tumor necrosis factor (TNF)-alpha and IL-10 production in a lipopolysaccharide (LPS)-induced cytokine production model in mice. These results indicate that FR234938 has potential anti-inflammatory activity. Non-nucleoside Adenosine Deaminase Inhibitor FR234938 has good potential as a new type of anti-rheumatic and anti-inflammatory drug, by modulating host-defense concentrations of Adenosine.
-
a highly potent non nucleoside Adenosine Deaminase Inhibitor efficient drug discovery by intentional lead hybridization
Journal of the American Chemical Society, 2004Co-Authors: Tadashi Terasaka, Masako Kuno, Takayoshi Kinoshita, Isao NakanishiAbstract:We disclose herein the rapid discovery of the first highly potent (Ki = 7.7 nM) non-nucleoside Adenosine Deaminase (ADA) Inhibitor based on the rational hybridization of two structurally distinct leads. Two micromolar Inhibitors were discovered by a parallel rational design and random screening program, and individual crystal structures of bovine ADA in complexation with these Inhibitors revealed several unknown binding sites and distinct binding modes. Using this information as the starting point, highly effective lead hybridization was achieved in only two structure-based drug design iterations. The conceptual approach illustrated by this example promises to be broadly useful in the search for new chemical entities and can contribute greatly to improve the overall efficiency and speed of drug discovery.
Virgilio Mattoli - One of the best experts on this subject based on the ideXlab platform.
-
PMMA/Polysaccharides Nanofilm Loaded with Adenosine Deaminase Inhibitor for Targeted Anti-inflammatory Drug Delivery
2016Co-Authors: Eugenio Redolfi Riva, Andrea Desii, Stefania Sartini, Concettina La Motta, Barbara Mazzolai, Virgilio MattoliAbstract:A novel drug delivery vector, a free-standing polymeric ultrathin film (nanofilm) composed of PMMA and a polysaccharides multilayer, is presented. Chitosan and sodium alginate are alternatively deposited by spin-assisted LbL assembly onto a plasma-treated PMMA thin film. Hydrophobic anti-inflammatory drugs, an Adenosine Deaminase Inhibitor (APP) and its fluorescent dansyl derivate (APP-Dns), are encapsulated inside the LbL multilayer using a simple casting deposition procedure. The resulting drug loaded nanofilm can be suspended in water upon dissolution of a PVA sacrificial layer. Morphological characterization of the nanofilm shows that PMMA/LbL nanofilms possess nanometric thickness (
-
PMMA/Polysaccharides Nanofilm Loaded with Adenosine Deaminase Inhibitor for Targeted Anti-inflammatory Drug Delivery
Langmuir : the ACS journal of surfaces and colloids, 2013Co-Authors: Eugenio Redolfi Riva, Andrea Desii, Stefania Sartini, Concettina La Motta, Barbara Mazzolai, Virgilio MattoliAbstract:A novel drug delivery vector, a free-standing polymeric ultrathin film (nanofilm) composed of PMMA and a polysaccharides multilayer, is presented. Chitosan and sodium alginate are alternatively deposited by spin-assisted LbL assembly onto a plasma-treated PMMA thin film. Hydrophobic anti-inflammatory drugs, an Adenosine Deaminase Inhibitor (APP) and its fluorescent dansyl derivate (APP-Dns), are encapsulated inside the LbL multilayer using a simple casting deposition procedure. The resulting drug loaded nanofilm can be suspended in water upon dissolution of a PVA sacrificial layer. Morphological characterization of the nanofilm shows that PMMA/LbL nanofilms possess nanometric thickness (
-
pmma polysaccharides nanofilm loaded with Adenosine Deaminase Inhibitor for targeted anti inflammatory drug delivery
Langmuir, 2013Co-Authors: Eugenio Redolfi Riva, Andrea Desii, Stefania Sartini, Concettina La Motta, Barbara Mazzolai, Virgilio MattoliAbstract:A novel drug delivery vector, a free-standing polymeric ultrathin film (nanofilm) composed of PMMA and a polysaccharides multilayer, is presented. Chitosan and sodium alginate are alternatively deposited by spin-assisted LbL assembly onto a plasma-treated PMMA thin film. Hydrophobic anti-inflammatory drugs, an Adenosine Deaminase Inhibitor (APP) and its fluorescent dansyl derivate (APP-Dns), are encapsulated inside the LbL multilayer using a simple casting deposition procedure. The resulting drug loaded nanofilm can be suspended in water upon dissolution of a PVA sacrificial layer. Morphological characterization of the nanofilm shows that PMMA/LbL nanofilms possess nanometric thickness (<200 nm) and very low surface roughness (1–2 nm for drug loaded nanofilms and <1 nm for blank nanofilm). Drug loaded films exhibit a diffusion controlled release mechanism following the Korsmayer–Peppas release model, confirmed by the fit of release data with a characteristic power law. Drug release is impaired through the...
Anthony Poon - One of the best experts on this subject based on the ideXlab platform.
-
antinociceptive and anti inflammatory properties of an Adenosine kinase Inhibitor and an Adenosine Deaminase Inhibitor
European Journal of Pharmacology, 1999Co-Authors: Anthony Poon, Jana SawynokAbstract:Spinal administration of an Adenosine kinase Inhibitor, alone or in combination with an Adenosine Deaminase Inhibitor, produces antinociception in inflammatory pain tests. In the present study, we examined the antinociceptive and anti-inflammatory effects produced by the peripheral (intraplantar) administration of 5'-amino-5'-deoxyAdenosine (an Adenosine kinase Inhibitor), 2'-deoxycoformycin (an Adenosine Deaminase Inhibitor), and combinations of both agents in the carrageenan-induced thermal hyperalgesia and paw oedema model in the rat. When injected in the ipsilateral paw immediately prior to carrageenan injection, both agents produced antinociception only at the highest dose (1 micromol), whereas a reduction in paw swelling was evident at a lower dose (300 nmol). Significant augmentation in both the antinociceptive and anti-inflammatory effects was seen when 5'-amino-5'-deoxyAdenosine and 2'-deoxycoformycin were co-administered in equimolar doses at all dose levels. Both effects were mediated via activation of Adenosine receptors, as indicated by blockade by an Adenosine receptor antagonist. When administered into the contralateral paw, 1 micromol 5'-amino-5'-deoxyAdenosine+1 micromol 2'-deoxycoformycin produced prominent antinociception, indicating a systemic drug activity. There was only a modest reduction in paw oedema in the carrageenan-injected (ipsilateral) paw, suggesting that much of this activity was locally mediated. Reversal of systemic effects on thermal thresholds by an intrathecal Adenosine receptor antagonist implicates a spinal site of action in this instance. An ipsilateral administration of 1 micromol 5'-amino-5'-deoxyAdenosine, but not 1 micromol 2'-deoxycoformycin, reduced carrageenan-induced c-Fos expression in the spinal dorsal horn, and this was further reduced by the peripheral co-injection of the two agents. These results provide evidence for a predominantly spinal antinociceptive effect and a predominantly peripheral anti-inflammatory effect produced by Inhibitors of Adenosine kinase and Adenosine Deaminase.
-
peripheral antinociceptive effect of an Adenosine kinase Inhibitor with augmentation by an Adenosine Deaminase Inhibitor in the rat formalin test
Pain, 1998Co-Authors: Jana Sawynok, Allison Reid, Anthony PoonAbstract:Abstract This study examined the ability of an Adenosine kinase Inhibitor (5′-amino-5′-deoxyAdenosine; NH2dAD), an Adenosine Deaminase Inhibitor (2′-deoxycoformycin), and combinations of these agents to produce a peripheral modulation of the pain signal in the low concentration formalin model. Drugs were administered in combination with 0.5% formalin, or into the contralateral hindpaw to test for systemic effects, and episodes of flinching behaviors determined. Coadministration of NH2dAD 0.1–100 nmol with formalin produced antinociception as revealed by an inhibition of flinching behaviors. This action was peripherally mediated as it was not seen following contralateral administration of the NH2dAD, and was due to accumulation of Adenosine and activation of cell surface Adenosine receptors as it was blocked by the Adenosine receptor antagonist caffeine. Antinociception was intensity-dependent, as it was not seen when higher concentrations of formalin (0.75%, 1.5%) were used. The coadministration of the selective Adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine revealed the presence of an Inhibitory tone of Adenosine when the intrinsic antinociceptive effect of NH2dAD was obscured by the solvent or the stimulus intensity. 2′-Deoxycoformycin 0.1–100 nmol did not produce any intrinsic effect, but 100 nmol coadministered with low concentrations of NH2dAD, which lacked an intrinsic effect, augmented antinociception by NH2dAD. Again, this was a peripheral rather than a systemic response. The combined action of the Adenosine kinase and Deaminase Inhibitors was completely reversed by coadministration of caffeine. Antinociception with NH2dAD is observed at higher concentrations of formalin in second trial experiments. This study demonstrates a peripheral antinociceptive action mediated by endogenous Adenosine which accumulates following the peripheral inhibition of Adenosine kinase; this action is due to activation of an Adenosine A1 receptor.
-
antinociception by Adenosine analogs and Inhibitors of Adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat
Pain, 1998Co-Authors: Anthony Poon, Jana SawynokAbstract:Abstract The present study examined the spinal antinociceptive effects of Adenosine analogs and Inhibitors of Adenosine kinase and Adenosine Deaminase in the carrageenan-induced thermal hyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of Adenosine kinase Inhibitors by an Adenosine Deaminase Inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2 mg/100 μ l), which consistently produced significant paw swelling and thermal hyperalgesia. Drugs were administered intrathecally, either by acute percutaneous lumbar puncture (individual agents and combinations) or via an intrathecal catheter surgically implanted 7–10 days prior to drug testing (antagonist experiments). N 6 -cyclohexylAdenosine (CHA; Adenosine A 1 receptor agonist; 0.01–1 nmol), 2-[ p -(2-carboxyethyl)phenylethylamino]-5′- N -ethylcarboxamidoAdenosine (CGS21680; Adenosine A 2A receptor agonist; 0.1–10 nmol), 5′-amino-5′-deoxyAdenosine (NH 2 dAdo; Adenosine kinase Inhibitor; 10–300 nmol), and 5-iodotubercidin (ITU; Adenosine kinase Inhibitor; 0.1–100 nmol) produced, to varying extents, dose-dependent antinociception. No analgesia was seen following injection of 2′-deoxycoformycin (dCF; an Adenosine Deaminase Inhibitor; 100–300 nmol). Reversal of drug effects by caffeine (non-selective Adenosine A 1 /A 2 receptor antagonist; 515 nmol) confirmed the involvement of the Adenosine receptor, while antagonism by 8-cyclopentyl-1,3-dimethylxanthine (CPT; Adenosine A 1 receptor antagonist; 242 nmol), but not 3,7-dimethyl-1-propargylxanthine (DMPX; Adenosine A 2A receptor antagonist; 242 nmol), evidenced an Adenosine A 1 receptor mediated spinal antinociception by NH 2 dAdo. dCF (100 nmol), which was inactive by itself, enhanced the effects of 10 nmol and 30 nmol NH 2 dAdo. Enhancement of the antinociceptive effect of ITU by dCF was less pronounced. None of the antinociceptive drug regimens had any effect on paw swelling. These results demonstrate that both directly and indirectly acting Adenosine agents, when administered spinally, produce antinociception through activation of spinal Adenosine A 1 receptors in an inflammatory model of thermal hyperalgesia. The spinal antinociceptive effects of selected Adenosine kinase Inhibitors can be significantly augmented when administered simultaneously with an Adenosine Deaminase Inhibitor.
John W. Phillis - One of the best experts on this subject based on the ideXlab platform.
-
effects of an Inhibitor of Adenosine Deaminase deoxycoformycin and of nucleoside transport propentofylline on post ischemic recovery of adenine nucleotides in rat brain
Neurochemical Research, 1996Co-Authors: John W. Phillis, M H OreganAbstract:The effects of an Adenosine Deaminase Inhibitor (deoxycoformycin, 500 μg/kg) and of an Inhibitor of nucleoside transport (propentofylline, 10 mg/kg) on Adenosine and adenine nucleotide levels in the ischemic rat brain were investigated. The brains of the rats were microwaved before, at the end of a 20 min period of cerebral ischemia (4 vessel occlusion+hypotension), or after 5, 10, 45, and 90 min of reperfusion. Deoxycoformycin increased brain Adenosine levels during both ischemia and the initial phases of reperfusion. AMP levels were elevated during ischemia and after 5 min of reperfusion. ATP levels were elevated above those in the non-treated animals after 10 and 45 min of reperfusion. ADP levels were elevated above the non-drug controls at 90 min. These increases in ATP, ADP and AMP resulted in significant increases in total adenylates during ischemia, and after 10 min and 90 min of reperfusion. Propentofylline administration resulted in enhanced AMP levels during ischemia but did not alter Adenosine or adenine nucleotide levels during reperfusion in comparison with non-treated controls.
-
Deoxycoformycin and oxypurinol : protection against focal ischemic brain injury in the rat
Brain research, 1992Co-Authors: Yu Lin, John W. PhillisAbstract:Abstract We have previously demonstrated that oxypurinol (40 mg/kg i.p.), a xanthine oxidase Inhibitor, can reduce focal ischemic brain injury in the rat when applied pre-ischemically. By using a model of occlusion of the middle cerebral artery (MCA) in tandem with occlusion of the ipsilateral carotid artery, the present study further demonstrates that delayed (60 min) administration of oxypurinol also exhibits a protective action on ischemic damage in the stroked rat brain. Oxypurinol significantly reduced the ischemic cerebral infarct zone by preventing the development of brain damage primarily in areas distant to the central lesion core. A corresponding amelioration of brain swelling and attenuation of neurological deficits were evident. Similar protection against focal ischemic brain damage was evident when the Adenosine Deaminase Inhibitor, deoxycoformycin (500 μg/kg), was administered prior to the onse of ischemia. However, with delayed (60 min) administration deoxycoformycin had no protective effect. These findings support the hypothesis that manipulation of Adenosine catabolism can be an effective therapeutic approach to the prevention or treatment of brain injuries, such as those occuring during ischemic stroke or cardiac arrest.
-
Brain Adenosine and transmitter amino acid release from the ischemic rat cerebral cortex: effects of the Adenosine Deaminase Inhibitor deoxycoformycin.
Journal of neurochemistry, 1991Co-Authors: John W. Phillis, Gary A. Walter, R.e. SimpsonAbstract:The effects of a potent Adenosine Deaminase Inhibitor, deoxycoformycin, on purine and amino acid neuro-transmitter release from the ischemic rat cerebral cortex were studied with the cortical cup technique. Cerebral ischemia (20 min) was elicited by four-vessel occlusion. Purine and amino acid releases were compared from control ischemic animals and deoxycoformycin-pretreated ischemic rats. Ischemia enhanced the release of glutamate, aspartate, and gamma-aminobutyric acid into cortical perfusates. The levels of Adenosine, inosine, hypoxanthine, and xanthine in the same perfusates were also elevated during and following ischemia. Deoxycoformycin (500 micrograms/kg) enhanced ischemia-evoked release of Adenosine, indicating a marked rise in the Adenosine content of the interstitial fluid of the cerebral cortex. Inosine, hypoxanthine, and xanthine levels were depressed by deoxycoformycin. Deoxycoformycin pretreatment failed to alter the pattern of amino acid neurotransmitter release from the cerebral cortex in comparison with that observed in control ischemic animals. The failure of deoxycoformycin to attenuate amino acid neurotransmitter release, even though it markedly enhanced Adenosine levels in the extracellular space, implies that the amino acid release during ischemia occurs via an Adenosine-insensitive mechanism. Inhibition of excitotoxic amino acid release is unlikely to be responsible for the cerebroprotective actions of deoxycoformycin in the ischemic brain.
