RÉSUMÉ
Aiming at a better understanding of the role of A(2A) in temporal lobe epilepsy (TLE), we characterized the effects of the A(2A) antagonist SCH58261 (7-(2-phenylethyl)-5-amino-2(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) on seizures and neuroprotection in the pilocarpine model. The effects of SCH58261 were further analyzed in combination with the A(1) agonist R-Pia (R(-)-N(6)-(2)-phenylisopropyl adenosine). Eight groups were studied: pilocarpine (Pilo), SCH+Pilo, R-Pia+Pilo, R-Pia+SCH+Pilo, Saline, SCH+Saline, R-Pia+Saline, and R-Pia+SCH+Saline. The administration of SCH58261, R-Pia, and R-Pia+SCH58261 prior to pilocarpine increased the latency to SE, and decreased either the incidence of or rate of mortality from SE compared with controls. Administration of R-Pia and R-Pia+SCH58261 prior to pilocarpine reduced the number of Fluoro-Jade B-stained cells in the hippocampus and piriform cortex when compared with control. This study showed that pretreatment with R-Pia and SCH58261 reduces seizure occurrence, although only R-Pia has neuroprotective properties. Further studies are needed to clarify the neuroprotective role of A(2A) in TLE.
Sujet(s)
Récepteur A1 à l'adénosine/métabolisme , Récepteur A2A à l'adénosine/métabolisme , État de mal épileptique/métabolisme , Adénosine/pharmacologie , Analyse de variance , Animaux , Encéphale/anatomopathologie , Numération cellulaire , Modèles animaux de maladie humaine , Interactions médicamenteuses , Fluorescéines , Mâle , Dégénérescence nerveuse/étiologie , Dégénérescence nerveuse/métabolisme , Dégénérescence nerveuse/anatomopathologie , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Composés chimiques organiques/métabolisme , Phénylisopropyladénosine/pharmacologie , Phénylisopropyladénosine/usage thérapeutique , Pilocarpine/toxicité , Pyrimidines/usage thérapeutique , Rats , Rat Wistar , Temps de réaction/effets des médicaments et des substances chimiques , État de mal épileptique/induit chimiquement , État de mal épileptique/traitement médicamenteux , État de mal épileptique/anatomopathologie , Triazoles/usage thérapeutiqueRÉSUMÉ
Nerve ligation injury may produce a tactile allodynia. Intrathecal adenosine receptor agonists or morphine have an antiallodynic effect. In this study, we examined the effect of intrathecal morphine on the antiallodynic state induced by the adenosine A1 receptor agonist, N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), in a rat model of nerve ligation injury. Rats were prepared with ligation of left L5-6 spinal nerves and intrathecal catheter implantation. Tactile allodynia was measured by applying von Frey filaments to the lesioned hindpaw. Thresholds for withdrawal response were assessed. Morphine and R-PIA were administered to obtain the dose-response curve and the 50% effective dose (ED(50)). Fractions of ED(50)s were administered concurrently to establish the ED(50) of the drug combination. The drug interaction was analyzed using the isobolographic method. Intrathecal 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1 receptor antagonist, and naloxone were administered to examine the reversal of the antiallodynic effect. Side effects were also observed. Intrathecal morphine and R-PIA and their combination produced a dose-dependent antagonism without severe side effects. Intrathecal morphine synergistically enhanced the antiallodynic effect of R-PIA when coadministered. Intrathecal naloxone and DPCPX reversed the maximal antiallodynic effect in the combination group. These results suggest that activation of mu-opioid and A1 receptors at the spinal level is required for the synergistic interaction on tactile allodynia.
Sujet(s)
Agonistes du récepteur A1 à l'adénosine , Analgésiques morphiniques/usage thérapeutique , Morphine/usage thérapeutique , Douleur/traitement médicamenteux , Neuropathies périphériques/complications , Phénylisopropyladénosine/usage thérapeutique , Analgésiques morphiniques/administration et posologie , Animaux , Rythme circadien , Relation dose-effet des médicaments , Synergie des médicaments , Injections rachidiennes , Ligature , Mâle , Morphine/administration et posologie , Naloxone/pharmacologie , Antagonistes narcotiques/pharmacologie , Douleur/étiologie , Mesure de la douleur/effets des médicaments et des substances chimiques , Phénylisopropyladénosine/administration et posologie , Rats , Rat Sprague-Dawley , Xanthines/usage thérapeutiqueRÉSUMÉ
The antihypoxic activity of Allium sativum clove (garlic) aqueous and methanolic extracts was studied in mice. The extracts of garlic showed that the antihypoxic effect was dose-dependent. The minimum effective doses of aqueous and methanolic extracts were 0.2 g/kg and 5.12 g/kg, respectively. Phenytoin, 50 mg/kg, and R-phenylisopropyladenosine (R-PIA), 1.6 mg/kg (R-PIA) as positive controls increased survival time up to 52.5 +/- 2.9 min and 120.5 +/- 6 min, respectively, compared to normal saline (34.73 +/- 0.71 min). The high doses of aqueous (16.9 g/kg) and methanolic (12.8 g/kg) extracts increased survival time up to 73.17 +/- 4.9 and 68.41 +/- 3.7, respectively. These results indicated that the extracts of A. sativum cloves have a protective effect against hypoxia-induced lethality in mice.
Sujet(s)
Ail , Hypoxie cérébrale/métabolisme , Neuroprotecteurs/pharmacologie , Phytothérapie , Extraits de plantes/pharmacologie , Animaux , Relation dose-effet des médicaments , Femelle , Injections péritoneales , Mâle , Souris , Neuroprotecteurs/administration et posologie , Neuroprotecteurs/usage thérapeutique , Phénylisopropyladénosine/administration et posologie , Phénylisopropyladénosine/pharmacologie , Phénylisopropyladénosine/usage thérapeutique , Phénytoïne/administration et posologie , Phénytoïne/pharmacologie , Phénytoïne/usage thérapeutique , Extraits de plantes/administration et posologie , Extraits de plantes/usage thérapeutiqueRÉSUMÉ
BACKGROUND: There is often no satisfactory treatment for chronic pain after spinal cord injury. We have previously reported that intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) or the opioid morphine has anti-allodynic effects in a model of presumed chronic central pain after photochemically induced spinal cord injury in rats. In the present study, we set out to investigate the possible interaction between i.t. R-PIA and morphine in spinally injured rats. METHODS: Sprague-Dawley rats displaying allodynia-like behaviors to mechanical and cold stimuli after photochemically induced spinal cord injury with minor motor deficits were used. R-PIA and morphine, either alone or in combination, were administered i.t. through an implanted catheter to lumbar spinal cord. RESULTS: Cumulative doses of R-PIA or morphine dose-dependently reduced the mechanical allodynia-like behavior, with a threshold of 1 nmol and 1.5 nmol, respectively. When co-administrated, R-PIA and morphine produced marked suppression of mechanical allodynia at doses of 5 pmol and 7.5 pmol, respectively. The effect of i.t. co-administration of R-PIA and morphine on cold allodynia was comparable to i.t. R-PIA alone. The combination of R-PIA and morphine did not increase adverse effects such as motor deficits in comparison to either drug alone. CONCLUSION: These results demonstrate a supra-additive interaction between the adenosine A1-receptor agonist R-PIA and morphine to reduce mechanical allodynia-like behavior in rats with chronic spinal cord injury. The combination of R-PIA and morphine administered spinally may be superior to R-PIA or morphine alone for treating such pain.
Sujet(s)
Analgésiques morphiniques/usage thérapeutique , Morphine/usage thérapeutique , Douleur/traitement médicamenteux , Phénylisopropyladénosine/usage thérapeutique , Agonistes des récepteurs purinergiques P1 , Analgésiques morphiniques/administration et posologie , Animaux , Comportement animal/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Synergie des médicaments , Femelle , Injections rachidiennes , Morphine/administration et posologie , Douleur/psychologie , Phénylisopropyladénosine/administration et posologie , Rats , Rat Sprague-DawleyRÉSUMÉ
OBJECTIVE: The aim of this study was to determine whether selective activation of the adenosine A3 receptor reduces infarct size in a Langendorff model of myocardial ischemia-reperfusion injury. METHODS: Buffer-perfused rabbit hearts were exposed to 30 min regional ischemia and 120 min of reperfusion. Infarct size was measured by tetrazolium staining and normalized for area-at-risk (IA/AAR). RESULTS: Preconditioning by 5 min global ischemia and 10 min reperfusion reduced infarct size (IA/AAR) to 19 +/- 4% (controls: 67 +/- 5%). Replacing global ischemia with 5 min perfusion of the rabbit A3-selective agonist, IB-MECA (A3 Ki: 2 nM; A1 Ki: 30 nM) elicited a concentration-dependent reduction in infarct size; 50 nM IB-MECA reduced IA/AAR to 24 +/- 4%. The A1-selective agonist, R-PIA (25 nM) reduced IA/AAR to a similar extent (21 +/- 6%). However, while the cardioprotective effect of R-PIA was significantly inhibited (54 +/- 7% IA/AAR) by the rabbit A1-selective antagonist, BWA1433 (50 nM), the IB-MECA-dependent cardioprotection was unaffected (28 +/- 6% IA/AAR). A non-selective (A1 vs. A3) concentration of BWA1433 (5 microM) significantly attenuated the IB-MECA-dependent cardioprotection (61 +/- 7% IA/AAR). CONCLUSIONS: These data clearly demonstrate that selective A3 receptor activation provides cardioprotection from ischemia-reperfusion injury in the rabbit heart. Furthermore, the degree of A3-dependent cardioprotection is similar to that provided by A1 receptor stimulation or ischemic preconditioning.
Sujet(s)
Adénosine/analogues et dérivés , Ischémie myocardique/prévention et contrôle , Phénylisopropyladénosine/usage thérapeutique , Récepteurs purinergiques/effets des médicaments et des substances chimiques , Adénosine/usage thérapeutique , Animaux , Modèles animaux de maladie humaine , Mâle , Lésion de reperfusion myocardique/prévention et contrôle , Lapins , Activation chimiqueRÉSUMÉ
The influence of adenosine, its analogs: (-)N6-(R-phenylisopropyl)-adenosine (R-PIA), N6-cyclohexyladenosine (CHA), 5-(N-ethylcarboxamido)-adenosine (NECA), adenosine uptake inhibitor-dipyridamole, and theophylline and caffeine (adenosine receptor antagonists) on ethanol withdrawal syndrome was investigated in rats. Adenosine (100 mg/kg ip), all adenosine analogs and dipyridamole (30 mg/kg ip) reduced the number of rats in which audiogenic convulsions appeared. Caffeine and theophylline (5-25 mg/kg ip) did not influence significantly the audiogenic seizures, but they antagonized the depressing effects of adenosine analogs on these withdrawal symptoms. The results suggest that adenosine mechanisms in the brain may be implicated in the development of ethanol withdrawal syndrome.
Sujet(s)
Adénosine/analogues et dérivés , Adénosine/usage thérapeutique , Dépresseurs du système nerveux central/toxicité , Éthanol/toxicité , Récepteurs purinergiques P1/effets des médicaments et des substances chimiques , Syndrome de sevrage/traitement médicamenteux , Adénosine/administration et posologie , Adénosine/pharmacologie , Adénosine-5'-(N-éthylcarboxamide) , Animaux , Caféine/administration et posologie , Caféine/pharmacologie , Caféine/usage thérapeutique , Stimulants du système nerveux central/administration et posologie , Stimulants du système nerveux central/pharmacologie , Stimulants du système nerveux central/usage thérapeutique , Loi du khi-deux , Dipyridamole/administration et posologie , Dipyridamole/pharmacologie , Dipyridamole/usage thérapeutique , Modèles animaux de maladie humaine , Phénylisopropyladénosine/administration et posologie , Phénylisopropyladénosine/pharmacologie , Phénylisopropyladénosine/usage thérapeutique , Agonistes des récepteurs purinergiques P1 , Antagonistes des récepteurs purinergiques P1 , Rats , Crises épileptiques/traitement médicamenteux , Théophylline/administration et posologie , Théophylline/pharmacologie , Théophylline/usage thérapeutique , Vasodilatateurs/administration et posologie , Vasodilatateurs/pharmacologie , Vasodilatateurs/usage thérapeutiqueRÉSUMÉ
OBJECTIVE: The aim was to test whether infarct size limitation by adenosine A1 receptor activation is mediated by protein kinase C. METHOD: In the first series of experiments, myocardial infarction was induced in rabbits under pentobarbitone anaesthesia by 30 min coronary artery occlusion and 3 h reperfusion. Rabbits were pretreated with no drugs (control). 1 mg.kg-1 of R(-)N6-2-phenylisopropyl adenosine (PIA), 50 micrograms.kg-1 of staurosporine (Stauro), 2.5 mg.kg-1 of polymyxin B (PolyB), and a combination of PIA and either Stauro or PolyB. Infarct size and the area at risk were determined by tetrazolium staining and fluorescent particles, respectively. In the second series of experiments, the inotropic response to 4 beta-phorbol 12-myristate 13-acetate (PMA) was assessed in rabbits with and without pretreatment using the same doses of Stauro and PolyB as those in the first series of experiments. RESULTS: Infarct size expressed as percent of area at risk (%IS/AR) was significantly smaller in the PIA treated group than in the control: %IS/AR = 19.0(SEM 2.4)% v 37.7(4.0)%, P < 0.05. However, %IS/AR in the groups given Stauro [35.0(4.2)%], PolyB [37.9(3.2)%], PIA plus Stauro [34.9(3.9)%], and PIA plus PolyB [36.3(3.3)%] did not differ from the control value. PMA at the dose of 0.02 and 0.05 micrograms.kg-1 caused a dose dependent increase of the left ventricular dP/dtmax in the untreated rabbits. Such a positive inotropic response to PMA was not detected in rabbits pretreated with Stauro or PolyB, suggesting that the doses of the protein kinase C inhibitors were appropriate to block protein kinase C in the heart. CONCLUSIONS: Infarct size limitation by A1 receptor stimulation is mediated by activation of protein kinase C in pentobarbitone anaesthetised rabbits.
Sujet(s)
Alcaloïdes/pharmacologie , Infarctus du myocarde/prévention et contrôle , Phénylisopropyladénosine/usage thérapeutique , Polymyxine B/pharmacologie , Protéine kinase C/antagonistes et inhibiteurs , Animaux , Relation dose-effet des médicaments , Mâle , Infarctus du myocarde/métabolisme , Infarctus du myocarde/anatomopathologie , Myocarde/métabolisme , Myocarde/anatomopathologie , Lapins , Staurosporine , Activation chimique , 12-Myristate-13-acétate de phorbol/pharmacologieRÉSUMÉ
The selective A1- and A2-receptor agonists L-PIA (ED50 = 0.55-0.78 mmole/kg) and NEGA (D50 = 0.05-0.1 mmole/kg) possess high antihypoxic and radioprotective effects. A2-subtype receptors may be involved in the antihypoxic and radioprotective effects of adenosine analogs.
Sujet(s)
Hypoxie/traitement médicamenteux , Lésions radiques expérimentales/traitement médicamenteux , Radioprotecteurs/usage thérapeutique , Récepteurs purinergiques/effets des médicaments et des substances chimiques , Maladie aigüe , Adénosine/analogues et dérivés , Adénosine/usage thérapeutique , Adénosine-5'-(N-éthylcarboxamide) , Animaux , Évaluation préclinique de médicament , Femelle , Hypoxie/mortalité , Souris , Souris de lignée C57BL , Souris de lignée CBA , Phénylisopropyladénosine/usage thérapeutique , Lésions radiques expérimentales/mortalité , Rats , Rat WistarRÉSUMÉ
Rats subjected to restraint stress developed gastric lesions that could be reduced by R-phenylisopropyladenosine (R-PIA) administered intracerebroventricularly. This protective effect was reversed by 8-sulfophenyltheophylline given centrally, and by peripherally administered 8-phenyltheophylline. These results suggest that central adenosine receptors mediate the effect. In subsequent studies it was found that if the absolute level of ulcer formation in control rats was low, R-PIA had no ulcer protective effect. Thus, although it appears that adenosine receptors are important in attenuating pathological gastric responses to stress, this attenuation seems to be dependent on the level of ulcer formation in control animals.
Sujet(s)
Adénosine/analogues et dérivés , Anxiolytiques/usage thérapeutique , Ulcère gastrique/prévention et contrôle , Stress physiologique/complications , Adénosine/usage thérapeutique , Animaux , Injections ventriculaires , Mâle , Phénylisopropyladénosine/usage thérapeutique , Rats , Lignées consanguines de rats , Récepteurs purinergiques/effets des médicaments et des substances chimiques , Ulcère gastrique/étiologie , Théophylline/analogues et dérivés , Théophylline/pharmacologieRÉSUMÉ
The ability of various drugs to prevent the onset of status epilepticus induced by administration of the muscarinic agonist, pilocarpine, to lithium-pretreated rats was determined. Motor limbic seizures and status epilepticus occurred in 100% of rats administered pilocarpine (30 mg/kg, s.c.) 20 h after pretreatment with lithium (3 meq/kg, i.p.). The latency to spike activity and to status epilepticus was 20 +/- 1 min and 24 +/- 1 min, respectively. Atropine, diazepam, phenytoin, carbamazepine, phenobarbital, paraldehyde, and L-phenylisopropyladenosine (L-PIA) prevented all phases of seizure activity induced by lithium/pilocarpine treatment. The initiation of status epilepticus was significantly prolonged by pretreatment with sodium valproate. These findings indicate that the seizures induced by administration of lithium and pilocarpine accurately model generalized tonic-clonic epilepsy. The anticonvulsant activity of L-PIA was prevented by prior treatment with the adenosine antagonist, theophylline. The latency to spike and seizure activity was decreased by theophylline, indicating that endogenous adenosine may have a tonic inhibitory influence on cholinergic neurons. Atropine, diazepam, phenobarbital, phenytoin, sodium valproate, L-PIA, and carbamazepine did not interrupt seizure activity when administered 60 min after pilocarpine (approximately 35 min after initiation of status epilepticus). When rats were administered paraldehyde at this time, status epilepticus was rapidly terminated and all rats survived. Thus, status epilepticus induced by lithium and pilocarpine provides a seizure model that is not responsive to conventional anticonvulsants.