n(6)-cyclohexyladenosine and Seizures

Adenosine has anticonvulsant effects in various models of seizures. Alpha-2 adrenoceptors have also demonstrated different effects in different models of epilepsy. In this study, the role of alpha-2 adrenoceptors in the anticonvulsant effects of adenosine in mice was determined according to the method of intravenous pentylenetetrazole-induced seizure. In this study, N(6)-cyclohexyladenosine (CHA) (a selective A1 receptor agonist), clonidine (an alpha-2 adrenoceptors agonist), yohimbine (an alpha-2 adrenoceptors antagonist) and 8-cyclopentyl-1,3-dimethylxanthine (8-CPT) (a selective A1 receptor antagonist) were used. CHA at doses of 0.5, 1 and 2mg/kg significantly increased seizure threshold with the maximum anticonvulsant effect at 2mg/kg. Yohimbine (0.1, 1 and 10mg/kg), clonidine (0.1, 0.5, 1 and 2mg/kg) and 8-CPT (0.5, 1, 2 and 4mg/kg) had no effect on seizure by itself. Combination of yohimbine (10mg/kg) and CHA (0.25mg/kg) increased clonic seizure latency showing that yohimbine and CHA have an additive effect. Increasing the seizure threshold created by combining ineffective doses of yohimbine (10mg/kg) and CHA (0.25mg/kg) was completely inhibited by 8-CPT (4mg/kg) or clonidine (1 and 2mg/kg). Clonidine (0.5, 1 and 2mg/kg) inhibited the anticonvulsant effects of CHA (2mg/kg). Combination of 8-CPT (1mg/kg) and clonidine (0.5mg/kg) which completely inhibited the anticonvulsant effect of CHA (2mg/kg) indicates that 8-CPT and clonidine have an additive effect. In conclusion, adenosine and yohimbine exhibit an additive effect on the enhancement of the pentylenetetrazole-induced seizure threshold in mice, indicating the interaction of alpha-2 adrenoceptors and A1 adenosine receptors.

Topics: Adenosine; Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Animals; Anticonvulsants; Clonidine; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Pentylenetetrazole; Receptor, Adenosine A1; Receptors, Adrenergic, alpha-2; Seizures; Theophylline; Yohimbine

Adenosine agonists or low doses of morphine exert anti-convulsant effects in different models of seizures. On the other hand, a tight interaction has been reported between morphine and adenosine in various paradigms. This study investigated the effect of the interaction of adenosine and morphine on seizure susceptibility in the intravenous mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. The researchers used acute systemic administration of morphine, N(6)-cyclohexyladenosine (CHA) (a selective A1 receptor agonist), naltrexone (an opioid receptor antagonist) and 8-Cyclopentyl-1,3-dimethylxanthine (8-CPT) (a selective A1 receptor antagonist). Acute administration of morphine (0.25, 0.5 and 1 mg/kg) or CHA (0.25, 0.5, 1, 2 and 4 mg/kg) raised the threshold of seizures induced by PTZ. Non-effective dose of 8-CPT (2 mg/kg) inhibited the anticonvulsant effects of CHA (0.5 and 1 mg/kg). Combination of sub-effective doses of morphine (0.125 mg/kg) and CHA (0.125 mg/kg) increased clonic seizure latency showing the additive effect of morphine and CHA. The enhanced latency induced by combination of low doses of morphine and CHA completely reversed by 8-CPT (2 mg/kg) or naltrexone (1 mg/kg). Moreover, 8-CPT (2 mg/kg) inhibited anticonvulsant effects of morphine (0.25 and 0.5 mg/kg) and naltrexone (1 mg/kg) inhibited anticonvulsant effects of CHA (0.25, 0.5 and 1 mg/kg). Combination of low doses of 8-CPT (1 mg/kg) and naltrexone (0.5 mg/kg) inhibited the anticonvulsant effect of CHA (0.5 and 1 mg/kg). In conclusion, adenosine and morphine exhibit an additive effect on the enhancement of the pentylenetetrazole-induced seizure threshold in mice, probably through A1 or μ receptors.

Topics: Adenosine; Animals; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Morphine; Naltrexone; Narcotic Antagonists; Pentylenetetrazole; Seizures; Xanthines

The hippocampus and piriform cortex have a critical role in seizure propagation. In this study, the role of adenosine A1 receptors of piriform cortex on CA1 hippocampal kindled seizures was studied in rats.. Animals were implanted with a tripolar electrode in the right hippocampal CA1 region and two guide cannulae in the left and right piriform cortex. They were kindled by daily electrical stimulation of hippocampus. In fully kindled rats, N6- cyclohexyladenosine (CHA; a selective adenosine A1 receptors agonist) and 1,3-dimethyl-8-cyclopenthylxanthine (CPT a selective adenosine A1 receptor antagonist) were microinfused into the piriform cortex. The animals were stimulated at 5, 15 and 90 minutes (min) after drug injection.. Obtained data showed that CHA (10 and 100 microM) reduced afterdischarge duration, stage 5 seizure duration, and total seizure duration at 5 and 15 min after drug injection. There was no significant change in latency to stage 4 seizure. CPT at concentration of 20 microM increased afterdischarge duration, stage 5 seizure duration, and total seizure duration and decreased latency to stage 4 seizure at 5 and 15 min post injection. Pretreatment of rats with CPT (10 microM), 5 min before CHA (100 microM), reduced the effect of CHA on seizure parameters.. These results suggested that activity of adenosine A1 receptors in the piriform cortex has an anticonvulsant effect on kindled seizures resulting from electrical stimulation of the CA1 region of the hippocampus.

Topics: Adenosine; Analysis of Variance; Animals; Disease Models, Animal; Drug Interactions; Electric Stimulation; Electroencephalography; Entorhinal Cortex; Hippocampus; Kindling, Neurologic; Male; Microinjections; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1; Seizures; Time Factors; Xanthines

Adenosine exerts its anticonvulsants effect through different brain regions including piriform cortex. In this study, the effect of amygdala kindled seizures on adenosine A1 receptor-mediated neuromodulation in piriform cortex pyramidal neurons was tested at 24 h and 1 month after kindling. Animals were kindled by daily electrical stimulation of amygdala. Field potentials were recorded from layer II of piriform cortex pyramidal cells following stimulation of the lateral olfactory tract. Obtained results showed that N6-cyclohexyladenosine (CHA), a selective adenosine A1 receptor agonist (1, 10 and 100 microM; i.c.v.), reduced A1 slope and B1 amplitude of field potentials in both kindled and non-kindled (control) rats. However, its effects on kindled animals were more potent at 24 h, but not 1 month post-kindling. 8 cyclopenthyl-1,3-dimethylxanthine (CPT), a selective adenosine A1 receptor antagonist (50 microM, i.c.v.), had no significant effect on the field potential parameters. However, CPT (50 microM, i.c.v.) pretreatment eliminated effects of CHA (10 microM; i.c.v.) on the field potentials. These results indicate that activation of adenosine A1 receptors has an inhibitory effect on the field potentials of piriform cortex pyramidal neurons and the efficiency of adenosine A1 receptor neuromodulation in piriform cortex is increased at short-term (24 h) but return to normal at long-term (1 month) after kindling implementation.

Topics: Adenosine; Amygdala; Animals; Excitatory Postsynaptic Potentials; Kindling, Neurologic; Male; Olfactory Pathways; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1; Seizures; Theophylline

In this research the role of adenosine A1 and A2A receptors of the entorhinal cortex on piriform cortex kindled seizures was investigated. In piriform cortex kindled rats, N6-cyclohexyladenosine (CHA), a selective A1 receptor agonist, 1,3-dimethyl-8 cyclopenthylxanthine (CPT), a selective A1 receptor antagonist, CGS21680 hydrochloride (CGS), a selective A2A receptor agonist and ZM241385 (ZM), a selective A2A receptor antagonist were injected into the entorhinal cortex bilaterally. Five minutes later, animals were stimulated and seizure parameters were recorded. CHA (10 and 100microM) decreased the afterdischarge duration (ADD), stage 5 seizure duration (S5D), and seizure duration (SD), and increased the latency to stage 4 of the seizure (S4L) significantly. Bilateral microinjection of CPT (100microM) increased ADD, S(5)D, and SD, and reduced S(4)L significantly. Pretreatment of animals with CPT (50microM) before CHA (100microM), reduced the effect of CHA on seizure parameters. On the other hand, CGS (1mM) increased only ADD. Bilateral microinjection of ZM had no effect on seizure parameters. However, pretreatment of animals with ZM (200microM) before CGS (1mM), eliminated the excitatory effect of CGS on seizure parameters. These results suggest that activation of A1 receptors of the entorhinal cortex has an anticonvulsant, but activation of A2A receptors of this region has a proconvulsive effect on piriform cortex kindled seizures.

Topics: Adenosine; Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Electric Stimulation; Electrodes, Implanted; Entorhinal Cortex; Kindling, Neurologic; Male; Microinjections; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1; Receptor, Adenosine A2A; Seizures; Triazines; Triazoles; Xanthines

In this study the role of adenosine A1 and A2A receptors of the hippocampal CA1 region on piriform cortex-kindled seizures was investigated in rats. Animals were kindled by daily electrical stimulation of piriform cortex. In fully kindled rats, N6-cyclohexyladenosine (CHA; a selective A1 receptor agonist), 1,3-dimethyl-8-cyclopenthylxanthine (CPT; a selective A1 receptor antagonist), CGS21680 hydrochloride (CGS, a selective A2A receptor agonist) and, ZM241385 (ZM, a selective A2A receptor antagonist) were microinfused bilaterally into the hippocampal CA1 region. Rats were stimulated and seizure parameters were measured. Obtained results showed that microinjection of CHA (10 and 100 microM) decreased the afterdischarge duration (ADD), stage 5 seizure duration (S5D) and seizure duration (SD), and significantly increased the latency to stage 4 (S4L). Intra-hippocampal CPT increased ADD at the dose of 20 microM. Pretreatment of rats with CPT (10 microM) before CHA (10 microM), significantly reduced the effect of CHA on seizure parameters. On the other hand, microinjection of CGS (200 and 500 microM) increased ADD, but of ZM had no effect on seizure parameters. Pretreatment of rats with ZM (50 microM) before CGS (500 microM), significantly reduced the effect of CGS on seizure parameters. The results suggest that the facilitatory role of the hippocampal CA1 region in relaying or spreading of piriform cortex kindled seizures is decreased by the activation of adenosine A1 receptors and increased by A2A receptors.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Cerebral Cortex; Electric Stimulation; Hippocampus; Kindling, Neurologic; Male; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1; Receptor, Adenosine A2A; Receptors, Purinergic P2; Seizures; Triazines; Triazoles; Xanthines

In this study the role of adenosine A(1) receptors of CA1 region of the hippocampus on amygdala-kindled seizures was investigated in rats. Results obtained showed that in kindled animals, bilateral injection of N(6)-cyclohexyladenosine (CHA), an adenosine A(1) receptor agonist, at doses of 0.1, 1 and 10 microM into the CA1 region of the hippocampus significantly decreased the afterdischarge duration and stage 5 seizure duration and increased the latency to stage 4 seizure, but there were no changes in seizure stage. Also, bilateral injection of 1,3-dimethyl-8-cyclopenthylxanthine (CPT), an adenosine A(1) receptor antagonist, at doses of 0.5 and 1 microM into the CA1 region of the hippocampus could not produce any changes in the seizure parameters. Intrahippocampal pretreatment of CPT (1 microM) before CHA (0.1 and 1 microM), reduced the effects of CHA on seizure parameters significantly. Thus, it may be suggested that CA1 region of the hippocampus plays an important role in spreading seizure spikes from the amygdala to other brain regions and activation of adenosine A(1) receptors in this region, participates in anticonvulsant effects of adenosine agonists.

Topics: Adenosine; Amygdala; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Hippocampus; Kindling, Neurologic; Male; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Seizures; Xanthines

The effects of angiotensin (ANG) III and ANG IV on pentylenetetrazol (PTZ) seizure susceptibility--threshold and kindling in mice--as well as the influence of adenosine A(1) receptor agents (agonist and antagonist) on these effects were studied. It was found that ANG III and ANG IV increased dose-dependently the PTZ seizure threshold and decreased the seizure intensity in PTZ kindled mice. Cyclohexyladenosine (CHA), an adenosine A(1) receptor agonist, potentiated the effects of ANG III and ANG IV on the seizure threshold and kindling, whereas DPCPX (an A(1) receptor antagonist) reversed peptide-induced effects on the PTZ kindling. Taken together, ANG III and ANG IV decrease the PTZ seizure susceptibility. We could suggest that these effects are realized in part through interaction with adenosine A(1) receptors.

Topics: Adenosine; Angiotensin II; Angiotensin III; Angiotensins; Animals; Brain; Convulsants; Disease Susceptibility; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Kindling, Neurologic; Male; Mice; Mice, Inbred ICR; Pentylenetetrazole; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Seizures; Xanthines

Effects of intraperitoneal and intraamygdala N(6)-cyclohexyladenosine (CHA), a selective adenosine A(1) receptor agonist, and 1,3-dimethyl-8-cyclopentylxanthine (CPT), a selective adenosine A(1) receptor antagonist, were examined in fully hippocampal kindled rats. Intraperitoneal administration of CHA (0. 25, 0.5 and 1 mg/kg) decreased hippocampal secondary afterdischarge duration (SAD) and amygdala afterdischarge duration (ADD). Only the 1 mg/kg dose induced a significant increase in latency to stage 4. Intraperitoneal administration of CPT (0.25, 0.5 and 1 mg/kg) induced a significant increase in stage 5 duration, hippocampal SAD and ADD. Pretreatment of animals with CPT (1 mg/kg), antagonized effects of CHA on seizure parameters. Intraamygdala microinfusion (1 microl over 2 min) of CHA (5 nM-1 mM) significantly reduced hippocampal SAD and amygdala ADD. These effects were antagonized by intraamygdala CPT (1 microM). Results obtained suggest that in hippocampal kindled rats, amygdala may be regarded as a relay point for AD propagation specially in recruit activity of the hippocampus.

Topics: Adenosine; Amygdala; Animals; Anticonvulsants; Behavior, Animal; Dose-Response Relationship, Drug; Drug Antagonism; Electric Stimulation; Hippocampus; Injections, Intraperitoneal; Kindling, Neurologic; Male; Microinjections; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Reaction Time; Seizures; Xanthines

Melatonin (50 mg/kg; 60 min before the test) significantly raised the electroconvulsive threshold in mice. The protective action of melatonin (50 mg/kg) in the electroconvulsive threshold test was reversed by aminophylline, picrotoxin and bicuculline. Melatonin at the subconvulsive dose of 25 mg/kg potentiated the anticonvulsive activity of carbamazepine and phenobarbital (ED50 values were significantly decreased from 12.1 to 8.3 and from 18.9 to 11.8 mg/kg, respectively). No potentiation was observed in the case of valproate and diphenylhydantoin (their ED50s were changed from 253 to 249 and from 10.3 to 9.7 mg/kg, respectively). Melatonin did not influence the plasma or brain levels of anti-epileptics studied, so a pharmacokinetic interaction is not probable. Melatonin (25 mg/kg) alone and its combinations with carbamazepine or phenobarbital, providing a 50% protection against maximal electroshock, were devoid of significant motor adverse effects, but caused strong long-term memory deficit. Consequently, it does not seem to be a good candidate for the treatment of epilepsy.

Topics: Adenosine; Animals; Anticonvulsants; Avoidance Learning; Brain; Drug Interactions; Electroshock; Female; Melatonin; Mice; Psychomotor Performance; Seizures

One of the most dangerous aspects of theophylline toxicity is seizures. A review of the literature suggests that current anticonvulsant therapy remains far from optimal. As it is known that some of the pharmacologic effects of theophylline occur via antagonism of the adenosine A1 receptor, we tested the hypothesis that agonists acting at the adenosine A1 receptor can inhibit seizures caused by toxic doses of theophylline in mice. Dose-response curves were constructed for the ability of theophylline to produce tonic seizures in animals pre-treated with vehicle or several adenosine A1 receptor agonists. The LD50 (95% CI) for each dose-response curve was calculated. The results of these experiments showed that pretreatment with the direct-acting adenosine A1 agonists carbamazepine and cyclohexyladenosine and the indirect-acting agonist dipyridamole each failed to inhibit the ability of theophylline to cause tonic seizures (p > 0.05). Failure of these drugs to protect against theophylline-induced seizures suggests these seizures are produced by other mechanisms. Based on our results, adenosine A1 agonists, such as carbamazepine, appear to offer no therapeutic benefit in the treatment of theophylline-induced seizures.

Topics: Adenosine; Animals; Carbamazepine; Dipyridamole; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Lethal Dose 50; Male; Mice; Receptors, Purinergic P1; Seizures; Theophylline

The substantia nigra pars reticulata (SNr) has been reported to be critically involved in the development and propagation of epileptic seizures, while extracellular adenosine appears to be important for making seizures stop. In the present study, an adenosine A1 receptor agonist [N6-cyclohexyladenosine (CHA); 2.0 nmol/side, or vehicle] was injected bilaterally into the SNr shortly before each of the first five of a series of daily kindling stimuli delivered to the rat amygdala. Injections did not affect the acquisition of kindled afterdischarges or the rate at which seizures developed over subsequent kindling sessions, but convulsions occurring 48-72 h after treatment were significantly shortened. Thus, purinergic mechanisms in the SNr do not appear to be specifically involved in the acquisition of kindled seizures but may contribute to a postictal inhibitory process that shortens the convulsive component.

Topics: Adenosine; Animals; Electroencephalography; Injections; Kindling, Neurologic; Male; Rats; Seizures; Substantia Nigra

The seizure latency changed during daily pentylentetrazol (PTZ) induced convulsions showing an increase between days 2 and 4, a rapid decrease between days 5 and 10 and a slight increase again between days 11 and 14. At the respective timepoints, [3H]CHA binding, in cortex and cerebellum of PTZ treated animals followed exactly the same pattern, suggesting that the alterations in A1 receptors in these areas may partly determine the PTZ seizure latency curve. On the contrary, the changes of [3H]CHA binding in hippocampus (sustained increase) and striatum (sustained decrease) didn't follow the latency curve pattern. These results suggest that changes in A1 receptor density in specific brain areas may be involved in the modulation of seizure susceptibility.

Topics: Adenosine; Animals; Brain; Female; Mice; Mice, Inbred BALB C; Pentylenetetrazole; Reaction Time; Receptors, Purinergic; Seizures

The anticonvulsant actions of the adenosine receptor agonists, 1-phenylisopropyladenosine, 2-chloroadenosine and cyclohexyl-adenosine, against DMCM (methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate)-induced seizures in mice were studied with an infusion technique. 2-Chloroadenosine and cyclohexyladenosine were active at 1 mg/kg whereas 1-phenyl-isopropyladenosine was active at 0.03 mg/kg given i.p. At 10 mg/kg, 1-phenylisopropyladenosine was only weakly active against pentylenetetrazol-induced seizures and not active against bicuculline-induced seizures. The selective effect of 1-phenylisopropyladenosine against DMCM-induced seizures suggests that adenosine receptor agonists may allosterically counteract the negative modulating effect of DMCM on GABA coupling to the chloride channel. This indicates that adenosine receptors may have a physiological function within the GABA/benzodiazepine receptor complex in the brain.

Topics: 2-Chloroadenosine; Adenosine; Animals; Anticonvulsants; Bicuculline; Carbolines; Convulsants; Female; Mice; Pentylenetetrazole; Phenylisopropyladenosine; Receptors, Purinergic; Seizures; Theophylline

In the central nervous system, adenosine has been shown to be a major regulator of neuronal activity in convulsive disorders, mainly via the A1 receptor subtype. In a previous work, we have shown that seizures lead to an age-dependent upregulation of cerebral adenosine A1 sites measured in isolated rat cerebral membranes. However, information concerning regional changes in the receptor density was so far lacking. In the present study, the effects of bicuculline-induced seizures were investigated by quantitative autoradiography of central adenosine A1 receptors in developing rats and in adults. Animals were sacrificed 30 min after an intraperitoneal injection of either saline or a convulsive dose of bicuculline. Adenosine A1 receptors in brain sections were labeled by [3H]N6-cyclohexyladenosine (CHA), a potent receptor agonist. Generalized seizures induced a widespread increase in CHA-specific binding, with a marked enhancement in structures that mediate seizure activity, such as substantia nigra, amygdala, septum and hippocampus. Moreover, the addition of guanylyl-5'-imidodiphosphate, a GTP analogue, to the incubation medium reduced CHA binding by the same order of magnitude whether rats were given saline or bicuculline, suggesting that additional adenosine A1 receptors are also functionally linked to G proteins. The age-related postictal increase in adenosine receptors might contribute to facilitate adenosine anticonvulsant effect, especially in newborns.

Topics: Adenosine; Animals; Autoradiography; Bicuculline; Brain; Brain Chemistry; Female; GTP-Binding Proteins; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Male; Rats; Rats, Inbred Strains; Receptors, Purinergic; Seizures

Single and repeated Pentylentetrazol (PTZ)-induced convulsions are associated with significant changes of A1 adenosine receptors (detected using the radioligand [3H]cyclohexyladenosine, [3H]CHA) in 4 different brain areas of the mouse, namely cortex, hippocampus, cerebellum and striatum. In hippocampus and cerebellum, a rapid increase in [3H]CHA binding, by 26% and 30% respectively, was observed 1 h after a single PTZ convulsion. In striatum, on the contrary, a significant decrease by 30% in [3H]CHA binding was seen, whereas in cortex no significant change could be detected. After daily repeated PTZ convulsions, a significant increase of A1 receptors by 26% appeared also in cortex, while the changes of A1 receptors observed in the other brain areas after a single PTZ convulsion were maintained in almost the same range. All the alterations observed were due to changes of the total number of A1 receptors (Bmax) without changes in receptor affinity (Kd). A significant increase in the latency of PTZ seizure (time between the PTZ-injection and the beginning of the seizure) was also observed after repeated PTZ-induced convulsions at the time when the changes in A1 adenosine receptors were noted. Considered together, these results provide further evidence for an A1 receptor-mediated modulation of seizure susceptibility and indicate that specific brain areas may play different roles in this modulation. The binding of [3H]CHA to membranes from different cortical and subcortical areas of the epileptic mutant mouse 'tottering' was not different from that in control animals.

Topics: Adenosine; Animals; Brain; Epilepsy; Kinetics; Mice; Mice, Inbred BALB C; Mice, Neurologic Mutants; Organ Specificity; Pentylenetetrazole; Receptors, Purinergic; Seizures; Species Specificity

Effects of MK-801, adenosinergic agents and carbamazepine were investigated against hypoxic stress-induced convulsions and death in mice. MK-801, a N-methyl D-aspartate antagonist, offered a significant protective effect against hypoxic convulsions. Adenosinergic agents such as adenosine, 2-chloroadenosine, N6-cyclohexyladenosine and dipyridamole produced theophylline-sensitive protective effect as they dose-dependently prolonged the latencies for onset of convulsions and death. Pretreatment with adenosinergic agents and MK-801 markedly enhanced the protective effect of the stable analogs of adenosine namely, 2-chloroadenosine and N6-cyclohexyladenosine. However, pretreatment with combination of MK-801 and adenosine or dipyridamole did not show enhanced protective effect. Carbamazepine also exhibited dose-dependent theophylline-sensitive protective effect. The pretreatment with combination of carbamazepine and MK-801 showed significantly enhanced protective effect. The observed enhanced protective effect of MK-801 and adenosinergic agents was reversed by pretreatment with theophylline. These results indicate the possible involvement of adenosinergic mechanisms in preventing hypoxic stress-induced convulsions and the role of NMDA receptors in hypoxia-induced convulsions and death as MK-801 not only showed effect per se but also potentiated the response due to adenosinergic agents.

Topics: 2-Chloroadenosine; Adenosine; Animals; Carbamazepine; Dipyridamole; Dizocilpine Maleate; Drug Interactions; Female; Male; Mice; Seizures; Stress, Physiological; Theophylline

The mechanism of action of aminophylline in prolonging seizures was tested in amygdala-kindled rats. Aminophylline prolonged the afterdischarge duration of kindled seizures. This seizure-prolonging action of aminophylline was strongly antagonized by the adenosine A1 agonist cyclohexyladenosine and partially antagonized by the benzodiazepine partial agonist RO 15-1788. However, the specific benzodiazepine antagonist CGS 8216 did not affect the seizure-prolonging action of aminophylline. Also, the potent anticonvulsant effect of diazepam on kindled seizures, which was completely antagonized by CGS 8216, was unaffected by aminophylline. Furthermore, a range of benzodiazepine inverse agonists, GABA antagonists, phosphodiesterase inhibitors and xanthines did not prolong afterdischarge durations. These results demonstrate that the seizure-prolonging action of aminophylline is due to block of A1 adenosine receptors since it is prevented by adenosine A1 agonists.

Topics: Adenosine; Aminophylline; Amygdala; Animals; Brain; Carbolines; Diazepam; Flumazenil; Kindling, Neurologic; Male; Picrotoxin; Pyrazoles; Pyrrolidinones; Rats; Rats, Inbred Strains; Receptors, Purinergic; Rolipram; Seizures; Theophylline; Xanthines

The effect of adenosine agonist pretreatment on the seizure activity of caffeine was investigated in NIH Swiss mice. The seizure ED50 of caffeine alone was determined to be 223 mg/kg and this was reduced to 68 mg/kg following pretreatment with 0.30 mg/kg N-ethyl carboxamidoadenosine (NECA). Additionally, NECA dose-dependently increased the seizure potency of 100 mg/kg caffeine (a dose which is normally subconvulsant). A proconvulsant effect of NECA was also detected following intracerebroventricular administration of 2.5 ug NECA, however the same doses of N6-cyclohexyladenosine (CHA) and 2-chloroadenosine (2 C1-ADO) did not precipitate seizures. The data reveal proconvulsant actions of both peripherally and centrally administered NECA towards caffeine-induced seizures. Such actions need to be reconciled with the general anticonvulsant action of adenosine and adenosine agonists.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Anticonvulsants; Caffeine; Cerebral Ventricles; Dose-Response Relationship, Drug; Male; Mice; Premedication; Receptors, Purinergic; Regression Analysis; Seizures

The temporal requirements for theophylline-induced upregulation of A1 adenosine receptors and elevation of seizure threshold were examined. Chronic theophylline exposure (75 mg/kg twice daily) elicited a significant upregulation of [3H]cyclohexyladenosine ([3H]CHA) binding sites following 7 and 14 days of treatment. Alterations in seizure threshold followed a similar temporal pattern of development. The reversibility of theophylline-induced upregulation of high affinity [3H]CHA binding sites was complete at 10 days following cessation of theophylline administration, while the alteration of seizure threshold required 21 days to return to control values.

Topics: Adenosine; Animals; Bicuculline; Dose-Response Relationship, Drug; Male; Rats; Rats, Inbred Strains; Receptors, Purinergic; Seizures; Theophylline; Time Factors

This study investigates the ability of adenosine antagonists to reverse the anticonvulsant effects of carbamazepine on amygdala-kindled seizures in order to elucidate the possible physiological relevance of the potent effects of carbamazepine on adenosine receptors. At large but subconvulsant doses, neither caffeine nor theophylline altered the anticonvulsant potency of carbamazepine, even though caffeine by itself significantly increased the duration of the kindled afterdischarge. The adenosine agonist cyclohexyladenosine (CHA), administered intraperitoneally at a dose that produced sedation, had no effect on the kindled seizures. Although carbamazepine potently displaces the binding of several adenosine ligands in vitro, the present data do not suggest that the anticonvulsant effects of carbamazepine on amygdalakindled seizures are mediated by an adenosine agonist-like action.

Topics: Adenosine; Animals; Caffeine; Carbamazepine; Kindling, Neurologic; Male; Rats; Rats, Inbred Strains; Seizures; Theophylline

Topics: Adenosine; Animals; Cerebellum; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Purinergic; Seizures