2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Seizures

A stroke-like event follows seizures which may be responsible for the postictal state and a contributing factor to the development of seizure-induced brain abnormalities and behavioral dysfunction associated with epilepsy. Caffeine is the world's most popular drug with ∼85% of people in the USA consuming it daily. Thus, persons with epilepsy are likely to have caffeine in their body and brain during seizures. This preclinical study investigated the effects of acute caffeine on local hippocampal tissue oxygenation pre and post seizure. We continuously measured local oxygen levels in the CA1 region of the hippocampus and utilized the electrical kindling model in rats. Rats were acutely administered either caffeine, or one of its metabolites, or agonists and antagonists at adenosine sub-receptor types or ryanodine receptors prior to the elicitation of seizures. Acute caffeine administration caused a significant drop in pre-seizure hippocampal pO

Topics: Adenosine; Animals; CA1 Region, Hippocampal; Caffeine; Dose-Response Relationship, Drug; Hypoxia; Kindling, Neurologic; Male; Oxygen; Phenethylamines; Pyrimidines; Rats; Receptors, Adenosine A2; Seizures; Triazoles

Adenosine is a well-known endogenous modulator of neuronal excitability with anticonvulsant properties. Thus, the modulation exerted by adenosine might be an effective tool to control seizures. In this study, we investigated the effects of drugs that are able to modulate adenosinergic signaling on pentylenetetrazole (PTZ)-induced seizures in adult zebrafish. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) decreased the latency to the onset of the tonic-clonic seizure stage. The adenosine A1 receptor agonist cyclopentyladenosine (CPA) increased the latency to reach the tonic-clonic seizure stage. Both the adenosine A2A receptor agonist and antagonist, CGS 21680 and ZM 241385, respectively, did not promote changes in seizure parameters. Pretreatment with the ecto-5'nucleotidase inhibitor adenosine 5'-(α,β-methylene) diphosphate (AMPCP) decreased the latency to the onset of the tonic-clonic seizure stage. However, when pretreated with the adenosine deaminase (ADA) inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), or with the nucleoside transporter (NT) inhibitors, dipyridamole and S-(4-Nitrobenzyl)-6-thioinosine (NBTI), animals showed longer latency to reach the tonic-clonic seizure status. Finally, our molecular analysis of the c-fos gene expression corroborates these behavioral results. Our findings indicate that the activation of adenosine A1 receptors is an important mechanism to control the development of seizures in zebrafish. Furthermore, the actions of ecto-5'-nucleotidase, ADA, and NTs are directly involved in the control of extracellular adenosine levels and have an important role in the development of seizure episodes in zebrafish.

Topics: Adenine; Adenosine; Adenosine A1 Receptor Antagonists; Adenosine Diphosphate; Animals; Benzyl Compounds; Convulsants; Dipyridamole; Gene Expression Regulation; Genes, fos; Pentylenetetrazole; Phenethylamines; Phosphodiesterase Inhibitors; Seizures; Signal Transduction; Thioinosine; Xanthines; Zebrafish

In the present study, the effects of adenosine agonists on the development of sensitization to withdrawal signs precipitated after sporadic treatment with diazepam, in mice, were investigated. To obtain the sensitization, the animals were divided into groups: continuously and sporadically treated with diazepam (15.0 mg/kg, s.c.). The adenosine receptor agonists (CPA, CGS 21,680 and NECA) were administered in sporadically diazepam treated mice during two diazepam-free periods. Concomitant administration of pentetrazole (55.0 mg/kg, s.c.) with flumazenil (5.0 mg/kg, i.p.) after the last injection of diazepam or vehicle, induced the withdrawal signs, such as clonic seizures, tonic convulsion and death episodes. The major finding of our experiments is attenuation of withdrawal signs in sensitized mice, inducing by all adenosine agonists. Only higher dose of CPA produced significantly decreased the number of withdrawal incidents, while both used doses of CGS 21,680 and NECA produced more clear effects. These results support the hypothesis that adenosinergic system is involved in the mechanisms of sensitization to the benzodiazepine withdrawal signs, and adenosine A(2A) receptors play more important role in that process.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Adenosine A2 Receptor Agonists; Adenosine-5'-(N-ethylcarboxamide); Animals; Convulsants; Diazepam; Hypnotics and Sedatives; Male; Mice; Pentylenetetrazole; Phenethylamines; Purinergic P1 Receptor Agonists; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

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

The involvement of adenosine receptor agonists in benzodiazepine withdrawal signs was evaluated as the seizure susceptibility of mice. The concomitant administration of subthreshold dose of pentetrazole (55.0 or 60.0 mg/kg, s.c.) with flumazenil (10.0 mg/kg, i.p.) in mice chronically treated with temazepam or diazepam induced the appearance of withdrawal signs: clonic seizures, tonic convulsions and death episodes. The administration of the selective A1 (CPA-N6-cyclopentyladenosine), A2A (CGS 21680-2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride) and the non-selective A1/A2A (NECA-5'-N-ethylcarboxamidoadenosine) adenosine receptor agonists (i.p.) evoked the significant attenuation of benzodiazepine withdrawal signs, and these effects were more expressed in temazepam- than in diazepam-dependent mice. CPA has shown the most apparent and dose-dependent attenuating effect. The results confirm that adenosine A1 and A2A receptors are involved in benzodiazepine withdrawal signs, and adenosine A1 receptor plays a predominant role in this phenomenon.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Diazepam; Dose-Response Relationship, Drug; Flumazenil; Male; Mice; Pentylenetetrazole; Phenethylamines; Purinergic Agonists; Purinergic P1 Receptor Agonists; Purinergic P2 Receptor Agonists; Seizures; Substance Withdrawal Syndrome; Temazepam

In order to assess long-lasting consequences of recurrent seizures during development, the effects of repeated seizures in developing rats were investigated on brain adenosine A1 and A2A receptors. The characteristics of A1 and A2A receptors were analyzed by measuring the binding of the selective agonists [3H]CHA (N6-cyclohexyladenosine) and [3H]CGS 21680 (2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosine), respectively, on cerebral membrane preparations, whereas receptor coupling to G-proteins was examined by using a GTP analogue (Gpp(NH)p; guanylyl-5'-imidodiphosphate). Seizures were induced by bicuculline once a day at two different developmental stages: either from postnatal day 5 to postnatal day 7 (P5-P7) or from P15 to P17. Adenosine receptors were then studied at P15, P25 and P60. P5-P7 seizures led to an increase in A1 receptor density at P60 and to a decrease in their coupling to G-proteins at P15, but they did not affect A2A receptors. P15-P17 seizures decreased the coupling of A1 receptors to G-proteins at P25 and P60, reduced the density of A2A receptors at P25 and increased their affinity at P60. These results depict a persistent sensitivity of both A1 and A2A brain adenosine receptors to repeated seizures, with selective receptor alterations according to the cerebral maturational stage when seizures occur. In respect to the neuromodulatory and anticonvulsant properties of adenosine, such changes might be implicated in long-term functional brain reorganization after early seizures and future susceptibility to convulsive disorders.

Topics: Adenosine; Animals; Animals, Newborn; Bicuculline; Brain Chemistry; Convulsants; Female; Guanylyl Imidodiphosphate; In Vitro Techniques; Kinetics; Membranes; Phenethylamines; Pregnancy; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptors, Purinergic P1; Seizures

Focal injection of the adenosine A2A receptor agonist CGS21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethyl-carboxamidoaden osine) in the rat prepiriform cortex produced a reduction in the severity of bicuculline methiodide-induced motor seizures. The anticonvulsant effect of CGS21680 exhibited dose-dependency and modest potency (ED50 = 605 +/- 47 pmol/rat). Pharmacological characterization of the anticonvulsant response in the prepiriform cortex revealed a significant correlation between the potency of adenosine analogs as anticonvulsants and their respective affinities for adenosine A1 receptors in vitro. These results indicate that the low affinity of CGS21680 for adenosine A1 receptors is sufficient to account for the anticonvulsant activity of this compound in the rat prepiriform cortex.

Topics: Adenosine; Animals; Anticonvulsants; Antihypertensive Agents; Behavior, Animal; Bicuculline; Cerebral Cortex; Dose-Response Relationship, Drug; Male; Membranes; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Seizures; Xanthines

The actions of the highly selective A2 adenosine agonist, CGS 21680, in modulating kindled seizures and locomotor activity were examined. I.c.v. injections of CGS 21680 into the lateral cerebral ventricle in fully kindled rats were found to prolong the period of postictal EEG depression and reduce postictal spiking in a dose-dependent manner, while not affecting the behavioral seizure stage or afterdischarge duration. CGS 21680 injections also lead to a dose-related inhibition of locomotor activity in rats exposed to an open field apparatus compared to rats receiving control injections of saline. These observations implicate the involvement of the A2 adenosine receptor in postictal phenomena and the locomotor depressant actions of adenosine, but do not indicate a direct anticonvulsant activity following A2 activation.

Topics: Adenosine; Amygdala; Animals; Electroencephalography; Electrophysiology; Injections, Intraventricular; Kindling, Neurologic; Male; Motor Activity; Phenethylamines; Rats; Seizures