n(6)-cyclohexyladenosine and Epilepsy

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

Adenosine and adenosine analogues have potent anticonvulsant effects on various seizure models, including kindling, an animal model of temporal lobe epilepsy. It is now reported that binding of a specific ligand (cyclohexyladenosine) to adenosine A1 receptors is not changed in the cerebral cortex of kindled rats. However, the affinity of cyclohexyladenosine to adenosine receptors is significantly increased in the hippocampus. In addition, cyclohexyladenosine is slightly more potent to inhibit [3H]D-aspartate outflow from hippocampal synaptosomes taken from kindled than from control rats. Taken together, these data suggest that an increased affinity of adenosine to A1 receptors may play a role in the anticonvulsant effect of adenosine A1 analogues in the kindling model.

Topics: Adenosine; Animals; Aspartic Acid; Brain; Epilepsy; In Vitro Techniques; Kindling, Neurologic; Male; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Synaptosomes

Cyclic AMP accumulations elicited by adenosine analogues 2-chloroadenosine (2-CADO), R-N6-phenylisopropyladenosine (R-PIA), and N6-cyclohexyladenosine (CHA) were investigated in cortical slices of chronic iron-induced epileptic rats. Cyclic AMP accumulation was elicited 9- to 18-fold by 2-CADO and it was elicited 5- to 7-fold by either R-PIA or CHA; 2-CADO was more potent than R-PIA or CHA in eliciting cyclic AMP accumulation. The adenosine analogues elicited cyclic AMP accumulation in a dose-dependent manner, and the elicitation was inhibited by the adenosine antagonist 8-phenyltheophylline. The 2-CADO-elicited accumulation of cyclic AMP was greatly increased in the cortical region on the primary epileptic side, while the R-PIA- or CHA-elicited accumulation did not change in any cortical region. The deviation detected only in the 2-CADO-elicited accumulation of cyclic AMP may be due to the difference in relative potency for adenosine receptors of the adenosine analogues. The results suggest that adenosine receptor-mediated generation of cyclic AMP is altered in the primary region of iron-induced epileptic cortex, in which heterogeneous alterations in different adenosine receptor subtypes may occur in the epileptic process.

Topics: 2-Chloroadenosine; Adenosine; Animals; Cerebral Cortex; Chronic Disease; Cyclic AMP; Electroencephalography; Epilepsy; Ferrous Compounds; In Vitro Techniques; Male; Phenylisopropyladenosine; Rats; Rats, Wistar; Receptors, Purinergic P1

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