adenosine-5--(n-ethylcarboxamide) and Seizures

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH

Topics: Amino Alcohols; Animals; Anticonvulsants; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Mice; Models, Molecular; Molecular Structure; Rats; Seizures; Structure-Activity Relationship

Drug resistance in epilepsy is considered as a complicated and multifactorial problem. Poor penetration of antiepileptic drugs (AEDs) across blood-brain barrier (BBB) into the brain, which results in insufficient level of the drugs at the targeted brain region, has been discussed as one mechanism contributing to pharmacoresistance of epilepsies. Therefore, modulating permeability of BBB is the effective treatment strategy since it facilitates the entry of AEDs into the central nervous system (CNS). Recently, signaling through receptors for the adenosine has been identified as a potent modulator of BBB permeability. This paper aimed to investigate the effects of auxiliary application of adenosine receptor (AR) agonist on amygdala-kindled seizures in adult male Wistar rats. When fully kindled seizures were achieved by daily electrical stimulation of the amygdala, rats were randomly divided into three groups: control, phenytoin, and phenytoin (PHT)+5'-N-ethylcarboxamidoadenosine (NECA) groups. NECA (0.08 mg/kg, i.v.) was applied to the PHT+NECA group after the administration of PHT (75 mg/kg, i.p. on the first day; 50mg/kg, i.p. on the following 9 days). Intravenous infusion of NECA resulted in a significant increase in brain PHT levels as compared with the PHT treatment alone. On the other hand, the auxiliary application of NECA dramatically decreased the frequency of generalized seizures and seizure stage, shortened duration of afterdischarge and generalized seizures, as well as the elevated the afterdischarge threshold and generalized seizures threshold. Our study demonstrated that auxiliary application of AR agonist enhanced brain antiepileptic drug levels and strengthened the anticonvulsant properties of PHT against amygdala kindled seizures.

Topics: Adenosine-5'-(N-ethylcarboxamide); Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Electric Stimulation; Electroencephalography; Kindling, Neurologic; Male; Phenytoin; Purinergic P1 Receptor Agonists; Random Allocation; Rats, Wistar; Receptors, Purinergic P1; Seizures; Time Factors

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

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

7-Acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo-4,5H-2,3-benzodiazepine hydrochloride (LY 300164; a selective noncompetitive AMPA/kainate antagonist; 2 mg/kg) and N(6)-2-(4-aminophenyl)ethyl-adenosine (APNEA; a nonselective adenosine A(1)/A(3) receptor agonist; 2 and 3 mg/kg) significantly raised the threshold for electroconvulsions in mice. In contrast, 5'-N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine A(1)/A(2) receptor agonist; up to 1 mg/kg) did not affect the electroconvulsive threshold. The combined treatment of LY 300164 with NECA or APNEA was superior to single-drug medication as regards their protective action in this seizure model. Moreover, the combinations of LY 300164 with either NECA or APNEA were devoid of motor impairment, although they produced a significant long-term memory deficit. Measurement of the plasma levels of LY 300164 alone and in combination with APNEA or NECA did not suggest pharmacokinetic phenomena as an explanation for the interaction between these drugs. APNEA did not influence the plasma concentration of LY 300164. Moreover, NECA even significantly decreased the plasma levels of the AMPA/kainate antagonist. The present study clearly indicates a strong positive interaction in terms of anticonvulsant activity between LY 300164 and the drugs acting via adenosine receptors.

Topics: Adenosine-5'-(N-ethylcarboxamide); Animals; Avoidance Learning; Behavior, Animal; Benzodiazepines; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Combinations; Drug Interactions; Electroshock; Male; Mice; Psychomotor Performance; Purinergic P1 Receptor Agonists; Receptors, AMPA; Retention, Psychology; Seizures; Sensory Thresholds

The protective effects of the selective adenosine A1 receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA), the selective adenosine A2A receptor agonist, 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), and the non-selective agonist, 5'-N-ethylcarboxamidoadenosine (NECA) were studied against lethal seizures induced by intraperitoneal (i.p.) injection of pentylenetetrazole (80 mg/kg). In acute studies there was a dose-dependent reduction of lethal seizures, as shown by the low dose's protecting 50% of animals (PD50): 0.11, 0.05 and 0.05 mg/kg i.p. for CCPA, 2HE-NECA and NECA, respectively. In the repeated administration studies the animals received either vehicle or drug i.p. twice daily for 12 days. The drug doses were twice the PD50 value: 0.3 mg/kg for CCPA or 0.1 mg/kg for both 2HE-NECA and NECA. 2HE-NECA and NECA maintained their protective activity against pentylenetetrazole-induced seizures (63% or 60% vs. 60% or 58% in acute studies, respectively). Conversely, repeated treatment with CCPA resulted in a marked decrease of its effects (67% vs. 30% in acute studies; P < 0.05). The data indicate that in addition to adenosine A1 the A2A receptors also appear to be involved in the protection from seizures. The anticonvulsant effects induced by repeated stimulation of adenosine A1 receptors are subject to tolerance, whereas effects depending on adenosine A2A receptor activation are maintained.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Anticonvulsants; Dose-Response Relationship, Drug; Male; Pentylenetetrazole; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Seizures

L-phenylisopropyladenosine (L-PIA; a preferential A1 adenosine agonist-0.05 mg/kg) offered no protection against electroconvulsions in mice but potentiated the anticonvulsant action of diazepam and valproate against maximal electroshock-induced seizures, decreasing the respective ED50 values from 9.5 to 4.0 mg/kg and from 250 to 185 mg/kg. However, it remained without effect on the protective activity of phenobarbital, carbamazepine and diphenylhydantoin. 5'-N-ethylcarboxamidoadenosine (NECA; a preferential A2 adenosine agonist-0.5 mg/kg) potentiated the efficacy of valproate. On the other hand, NECA (1 mg/kg) diminished the anticonvulsant action of phenobarbital (ED50 was elevated from 16.5 to 20.5 mg/kg), possessing no effect upon the protective action of carbamazepine. In addition, papaverine (20 mg/kg) significantly enhanced the protective efficacy of valproate and up to 40 mg/kg remained without influence upon the protective action of carbamazepine. However, papaverine (20 and 40 mg/kg) inhibited the anticonvulsive potential of phenobarbital. In the light of the results obtained A1 and A2 adenosine receptor-mediated events seem to possess different influences upon the protective effects of antiepileptic drugs.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Anticonvulsants; Body Temperature Regulation; Diazepam; Electroshock; Female; Mice; Phenylisopropyladenosine; Receptors, Purinergic; Seizures; Valproic Acid

The actions of adenosine in modulating amygdala kindling were examined using the stable adenosine analog 5'-N'-ethylcarboxamidoadenosine (NECA) and caffeine, an adenosine antagonist. Systemically administered NECA was found to significantly reduce the rate of postictal spiking and to significantly increase the duration of postictal EEG depression in amygdala kindled rats. In contrast, systemically administered caffeine significantly increased kindled seizure duration and reduced the duration of postictal EEG depression. Systemic administration of the methylxanthine derivative, 8-sulfophenyl theophylline (8-PST), failed to block the effects of NECA on kindling. Since systemically administered 8-PST blocks peripheral adenosine receptors, but has only limited CNS activity, the effects of NECA appear to be centrally mediated. These observations further demonstrate a role for adenosine in postictal phenomena and support the hypothesis that a release of endogenous adenosine contributes to the termination of ongoing seizure activity.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Amygdala; Animals; Anticonvulsants; Caffeine; Electric Stimulation; Electrodes, Implanted; Electroencephalography; Kindling, Neurologic; Male; Rats; Seizures; Theophylline; Time Factors

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

Kainic acid (KA), microinjected unilaterally into the rat prepiriform cortex (PC), produces generalized motor seizures in a dose-dependent manner. The adenosine agonist N-ethylcarboxamidoadenosine (NECA), when co-injected with KA, protects against seizures in a dose-dependent and highly potent manner: ED50 = 25.6 +/- 2.1 pmol/rat. The seizure-suppressing effects of NECA are completely abolished by co-administration of the adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (8-pSPT), suggesting that adenosine receptor activation underlies the efficacy of NECA against KA seizures. Moreover, dilazep, an effective blocker of adenosine uptake, when co-administered with KA, provides significant protection against seizures. Together, these findings suggest that adenosine receptors may play an important role in the regulation of the inhibitory neuronal circuitry of this paleocortical brain area.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Dilazep; Kainic Acid; Limbic System; Male; Rats; Rats, Inbred Strains; Seizures; Theophylline

The protective effects of a series of stable adenosine analogs against generalized seizures initiated by focal injection of bicuculline methiodide into the rat prepiriform cortex (PPC) were studied by microinjection of these compounds into this brain area. The adenosine agonists, 5'-N-(ethyl)carboxamido-adenosine (NECA), cyclohexyladenosine, cyclopentyadenosine, 2-chloroadenosine and R- and S-phenylisopropyladenosine (R- and S-PIA), protected animals against seizures in a dose-dependent, and extremely potent manner. NECA, the most potent compound evaluated, completely prevented seizures at doses greater than or equal to 6.8 pmol. In contrast, heroic doses of the A2 selective ligand, 2-phenylaminoadenosine, afforded no protection against seizures. The rank order of potency of these compounds in suppressing seizures is as follows: NECA greater than cyclohexyladenosine greater than cyclopentyladenosine greater than or equal to R-PIA greater than 2-chloroadenosine greater than S-PIA much greater than 2-phenylaminoadenosine. These data suggest that the antiseizure activity of these compounds in the PPC results from activation of A1 adenosine receptors. Quantitative autoradiographic analysis of the distribution of tritiated adenosine agonists 30 min after microinjection in the PPC reveals that [3H]NECA diffuses to a significantly greater extent than R-[3H]PIA, which may contribute to the relatively greater potency of the former compound in suppressing bicuculline methiodide-induced seizures. These results suggest that adenosine A1 receptors may participate in the normal inhibitory regulation of the PPC, a forebrain area which may play a significant role in the pathobiology of epilepsy.

Topics: 2-Chloroadenosine; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Autoradiography; Bicuculline; Cerebral Cortex; Dose-Response Relationship, Drug; Male; Phenylisopropyladenosine; Rats; Rats, Inbred Strains; Receptors, Purinergic; Seizures

Male Long-Evans rats were stereotaxically implanted with a bipolar electrode in the central amygdala and with a stainless-steel cannula in the lateral cerebral ventricle. Rats were then kindled once daily until 3 consecutive Stage 5 kindled seizures were elicited. Adenosine analogues were injected into the lateral cerebral ventricle to examine their effects on behavioral seizures and afterdischarge duration following a kindling stimulus. 5'-N-ethylcarboxamidoadenosine (NECA) and (-)-N-(1-methyl-2-phenylethyl)-adenosine(L-phenylisopropyladenosine) (L-PIA) produced dose-related reductions of amygdaloid-kindled seizures with NECA exhibiting slightly more potent anticonvulsant activity than L-PIA. Parenteral injections of caffeine, at a dose which had no effect on seizure parameters, antagonized the anticonvulsant effects of NECA. These results are consistent with the notion that adenosine is a modulator of synaptic activity in the CNS and methylxanthines exert a specific antagonism of central adenosine receptors.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Amygdala; Animals; Anticonvulsants; Cerebral Ventricles; Dose-Response Relationship, Drug; Kindling, Neurologic; Male; Phenylisopropyladenosine; Rats; Seizures; Vasodilator Agents